Methods for treating eating disorders in patients via renal neuromodulation

ABSTRACT

Methods for treating eating disorders and for reducing a risk associated with developing an eating disorder in patients via therapeutic renal neuromodulation and associated systems. Renal sympathetic nerve activity can be attenuated to improve a patient&#39;s eating disorder status or risk of developing an eating disorder. The attenuation can be achieved, for example, using an intravascularly positioned catheter carrying a therapeutic assembly configured to modulate the renal sympathetic nerve.

CROSS-REFERENCE TO RELATED APPLICATION(S)

The present application is a continuation of U.S. patent applicationSer. No. 16/456,255, filed Jun. 28, 2019, and entitled, “METHODS FORTREATING EATING DISORDERS IN PATIENTS VIA RENAL NEUROMODULATION”, nowU.S. Pat. No. 11,413,084, which claims the benefit of and priority toU.S. Provisional Patent Application No. 62/693,906, filed Jul. 3, 2018,each of which is incorporated herein by reference in its entirety.

TECHNICAL FIELD

The present technology relates generally to systems, devices, andmethods for treating eating disorders and/or for reducing a riskassociated with developing an eating disorder in patients via renalneuromodulation.

BACKGROUND

An eating disorder is a mental condition characterized by abnormaleating habits that negatively affect a person's physical or mentalhealth. For some eating disorders, obsession with food, body weight, andbody shape can cause significant disruption to a person's quality oflife, and depending on the severity or the type of eating disorder, thenumber of symptoms and/or persistence (e.g., duration) of symptoms,these disorders can interfere with mental, physical and/or socialfunction in the affected person, thereby greatly impacting quality oflife. In the most severe cases, eating disorders can belife-threatening. The prevalence of anorexia nervosa, bulimia nervosaand binge-eating disorder among adults in the United States is estimatedto be about 1.2%, 2%, 5.5%, respectively, with women being much morelikely than men to be afflicted with an eating disorder. Furtherestimates suggest that 1 in 8 young women (e.g., under 20 years) developsome form of diagnosable eating disorder. In addition to physical andmental health impacts, eating disorders also have significant economicburden attributable to work absences and reduced productivity, as wellas direct health care costs to patients.

Eating disorders are typically treated with psychotherapy (e.g.,cognitive behavior therapy), physical intervention and, in somesituations, with medication. Despite current treatment options, however,the burden of eating disorders and other related mental healthconditions remains high. As eating disorders can have severepsychological, cognitive, physical, social and economic impact onpatients as well as families and society, there is a need for treatmentsthat effectively treat and/or manage eating-related disorders, includingthe severity of symptoms associated with such disorders. Furthermore,there is a need for treatments that effectively reduce the incidence ordevelopment of an eating disorder, or provide other improvements inprognosis and outcomes for patients having, or at risk of developing, aneating-related disorder.

BRIEF DESCRIPTION OF THE DRAWINGS

Many aspects of the present disclosure can be better understood withreference to the following drawings. The components in the drawings arenot necessarily to scale. Instead, emphasis is placed on illustratingclearly the principles of the present disclosure.

FIG. 1 is a conceptual illustration of the sympathetic nervous system(SNS) and how the brain communicates with the body via the SNS.

FIG. 2 is an enlarged anatomic view of nerves of a left kidney to formthe renal plexus surrounding the left renal artery.

FIG. 3 illustrates an intravascular neuromodulation system configured inaccordance with an embodiment of the present technology.

FIGS. 4A and 4B are anatomic views of the arterial vasculature andvenous vasculature, respectively, of a human.

FIG. 5 illustrates modulating renal nerves with a neuromodulation systemconfigured in accordance with an embodiment of the present technology.

FIG. 6 is a block diagram illustrating a method of modulating renalnerves in accordance with an embodiment of the present technology.

FIG. 7 is a block diagram illustrating a method for improving an eatingdisorder risk score for a patient in accordance with an embodiment ofthe present technology.

FIG. 8A is a display table illustrating results from a study todetermine the effects of renal denervation on cortical axon density andmean norepinephrine concentration in animal subjects.

FIG. 8B is a series of graphs illustrating the response correlationbetween normalized cortical axon area vs. norepinephrine concentrationand norepinephrine concentration vs. extent of nerve ablation along theartery of the animal subjects of FIG. 8A.

FIG. 9 illustrates an eating disorder risk score calculator fordetermining a patient's eating disorder risk score in accordance with anembodiment of the present technology.

DETAILED DESCRIPTION

The present technology is directed to methods for treating eatingdisorders, managing symptoms or sequelae associated with eatingdisorders, reducing a severity of eating disorders, and/or for reducinga risk associated with developing an eating disorder in patients viarenal neuromodulation. In certain embodiments, the present technology isdirected to beneficially improving one or more measurable physiologicalparameters associated with eating disorders in a patient via renalneuromodulation. Other embodiments of the present technology includeperforming therapeutically-effective renal neuromodulation on a patientto reduce a severity of neurobiological symptoms relating to an eatingdisorder. Further embodiments of the present technology includeperforming therapeutically-effective renal neuromodulation on a patientto reduce the risk of occurrence of an eating disorder in at-riskpatients.

In yet another embodiment, a patient having had one or more previousepisodes or diagnosis of an eating disorder can be treated withtherapeutically-effective renal neuromodulation to reduce a riskassociated with reoccurrence of the eating disorder or development ofanother eating disorder. In a particular embodiment, for example, thepatient has experienced one or more periods of eating disorderindicators (e.g., excessive thinking about food, body or weight) thatposes a measurable risk for experiencing a reoccurrence or a pattern ofsuch symptoms, but the patient does not currently meet the standard foran eating disorder diagnosis. In another particular embodiment, thepatient has had a previous, but not current, diagnosis of an eatingdisorder that poses a measurable risk for developing the same or adifferent related Axis I disorder (e.g., anxiety disorder, depression,etc.). In some embodiments, the patient exhibits one or more additionalrisk factors for the development of an eating disorder following atraumatic event, life change or stressful situation. Other embodimentsof the present technology include performing therapeutically-effectiverenal neuromodulation on a patient prior to the patient experiencing apotentially life-debilitating or life-threatening episode. For example,the patient may be diagnosed with anorexia, depression, an anxietydisorder (e.g., general anxiety disorder, post-traumatic stress disorder(PTSD), etc.) and/or other psychotic disorder, have had one or more lifethreatening episodes due to lack of eating, or in another embodiment,the patient may also be experiencing physical health issues related tochronic/uncontrollable stress.

The present technology is further directed to methods for reducing anincidence of cardiovascular disease or a cardiovascular event inpatients diagnosed with an eating disorder. In certain embodiments, forexample, the present technology is directed to improving one or moremeasurable physiological parameters associated with cardiovascularhealth in the patient experiencing eating disorder symptoms or having aneating disorder diagnosis via renal neuromodulation. Other embodimentsof the present technology include performing therapeutically-effectiverenal neuromodulation on a patient diagnosed with an eating disorder toreduce a severity of a cardiovascular condition. Further embodiments ofthe present technology include performing therapeutically-effectiverenal neuromodulation on a patient diagnosed with an eating disorder toreduce the risk of occurrence of a cardiovascular event in such patientin later life.

As discussed in greater detail below, therapeutically-effective renalneuromodulation can include rendering neural fibers inert, inactive, orotherwise completely or partially reduced in function. This result canbe electrically-induced, thermally-induced, or induced by anothermechanism during a renal neuromodulation procedure, e.g., a procedureincluding percutaneous transluminal intravascular access.

Specific details of several embodiments of the technology are describedbelow with reference to FIGS. 1-9 . The embodiments can include, forexample, modulating nerves proximate (e.g., at or near) a renal artery,a renal vein, and/or other suitable structures. Although many of theembodiments are described herein with respect to electrically-induced,thermally-induced, and chemically-induced approaches, other treatmentmodalities in addition to those described herein are within the scope ofthe present technology. Additionally, other embodiments of the presenttechnology can have different configurations, components, or proceduresthan those described herein. A person of ordinary skill in the art,therefore, will accordingly understand that the technology can haveother embodiments with additional elements and that the technology canhave other embodiments without several of the features shown anddescribed below with reference to FIGS. 1-9 .

As used herein, the terms “distal” and “proximal” define a position ordirection with respect to the treating clinician or clinician's controldevice (e.g., a handle assembly). “Distal” or “distally” can refer to aposition distant from or in a direction away from the clinician orclinician's control device. “Proximal” and “proximally” can refer to aposition near or in a direction toward the clinician or clinician'scontrol device.

I. EATING DISORDERS

Eating disorders are categorized by abnormal obsession with food,control of food intake, body weight and/or shape, and otherinappropriate relationships with food. As used herein “eating disorder”refers to any form of eating disorder or illness associated withabnormal eating habits or compulsive behaviors associated withovereating, undereating, or eating inappropriate or dangeroussubstances. As there are several forms of eating disorders that aredistinguished by a spectrum of symptom types and severity as well as thepersistence of the disorder in an affected individual,clinically-accepted diagnosis of an eating disorder, may be found in theAmerican Psychiatric Association defines the criteria in its Diagnosticand Statistical Manual of Mental Disorders (DSM-5). While occasionalabnormal eating episodes (i.e., overeating or lack of eating) are normaland/or can accompany periods of acute stress or result from a life eventor circumstance, an eating disorder can be characterized by symptomsthat are excessive, recurrent and/or non-temporary (e.g., longer than amonth). In some situations, patients can be afflicted with more than oneeating disorder. In all forms of eating disorders, however, affectedand/or susceptible individuals may develop ongoing (chronic), short-term(acute) or recurring eating disorder episodes with potential fordebilitating mental and physical health outcomes.

The most common form of eating disorder is binge-eating disorder, whichis characterized by recurrent binge eating episodes during which aperson feels a loss of control and marked distress over his or hereating. As a result, people with binge eating disorder can becomeoverweight or obese. In diagnosing a binge-eating disorder, a clinicianwould assess (1) if the patient's eating takes place in a discreteperiod of time (e.g., within any 2-hour period), (2) if the patient iseating an amount of food that is definitely larger than what most peoplewould eat in a similar period of time under similar circumstances, and(3) if the patient experiences a sense of lack of control over or whileeating during the episode (e.g., a feeling that one cannot stop eatingor control what or how much one is eating). Binge eating episodes wouldbe additionally associated with three or more of the followingindicators: eating much more rapidly than normal, eating until feelinguncomfortably full, eating large amounts of food when not feelingphysically hungry, eating alone because of feeling embarrassed by howmuch one is eating, and feeling disgusted with oneself, depressed orvery guilty afterward.

Bulimia Nervosa is also characterized by binge eating as discussedabove, but further includes compulsory behavior that causes theindividual to purge the food, such as, through self-induced vomiting,excessive use of laxatives or diuretics, by fasting, and/or throughexcessive exercise. People with bulimia can fall within the normal rangefor their weight, but they often fear gaining weight, want desperatelyto lose weight or are intensely unhappy with their body size and/orshape.

Anorexia Nervosa is characterized by significant and persistentreduction in food intake which leads to extremely low body weight in thecontext of age, sex and physical health. They present with a relentlesspursuit of thinness and have a distorted view of their body image alongwith an intense fear of gaining weight. Despite that afflictedindividuals are starved or severely malnourished, many people withanorexia see themselves as overweight.

Other feeding or eating disorders, as classified in the DSM-5, includepica and rumination disorders. Pica is the ingestion of non-nutritivesubstances (e.g., hair, chalk, paint chips, rocks, wood, metal, carpet,soap, etc.) deemed to be age inappropriate and occurring over at least aone-month period. Rumination is characterized by repeated, voluntaryregurgitation (e.g., spewing up or spitting up of food) for a period ofat least one month, and which is not attributable to vomiting or anyrelated medical or gastrointestinal condition.

Persons with chronic (e.g., at least one month, greater than 2 months,greater than 3 months, greater than 6 months, between about 1 month and1 year, or greater than 1 year, etc.), eating disorders (e.g., bingeeating, bulimia, anorexia, pica, rumination, among others) reportdifficulties with work, school, home, relationships and/or socialactivities, and numerous studies have shown that this category ofdisorders causes clinically significant distress or impairment insocial, occupational, or other important areas of functioning.

As discussed above, diagnosis of an eating disorder is based on theidentification of the clinical criteria (e.g., symptoms and signs) asset forth in DSM-5. Clinicians and other mental health practitionerstypically use conventionally accepted diagnostic test methods, such asscreening tools (e.g., for use during diagnostic interviews, patienthealth questionnaires, etc.) for identifying eating disorder risk,severity and diagnosis. These screening tools are typically focused oncore symptoms and indicators as set forth in DSM-5, but some screeningtools provide further diagnostic capability to determine symptomseverity, various specifiers, and/or other risk factors. For example,severity is typically determined by the degree of disability (e.g.,cognitive, physical, social, occupational, etc.) or pain experienced bythe patient as well as the duration of the symptoms. These screeningtools are also designed to differentiate eating disorders from othermental disorders (e.g., anxiety disorders, depressive disorders, etc.).For example, patients can be diagnosed with an eating disorder and/or ameasure of eating disorder severity can be determined using the EatingDisorder Examination Questionnaire (EDE-Q). Other questionnaires mightbe used to combine anxiety and depression measurements, such as theHamilton Anxiety Rating Scale, the Hospital Anxiety and Depression Scale(HADS), and the Patient Health Questionnaire (PHQ-ADS). As disclosedherein, such screening tools can be used to provide a risk score forpredicting a patient's eating disorder status with respect to disorderdiagnosis, eating disorder severity and/or identifying at-riskpopulations.

Certain risk factors have been identified that may make an individualmore likely (e.g., increase a risk) to develop an eating disorder duringtheir lifetime. For example, some identified risk factors for increasinga likelihood of developing an eating disorder include having a familyhistory and/or personal history of an eating disorder, depression, ananxiety disorder or other mental illness, experiencing adverse lifeevents (e.g., illness, abuse, loss of a loved one, unemployment,psychological trauma, etc.), having experienced prior traumatic events,being a childhood survivor of abuse, experiencing trauma duringchildhood, experiencing parental loss or separation, having a history ofsubstance abuse, experiencing a difficult relationship, being in astressful situation, experiencing a major life change, experiencing anextended period of stress (e.g., chronic stress), physically inactive,and female gender, among others. Other factors include certainpersonality traits. For example, narcissistic personality disorder andborderline personality disorder are both predictive risk factors foreating disorders.

Patients presenting with an eating disorder may also experience otheradverse mental and physical diseases and disorders. For example, eatingdisorders have high comorbidity with mental disorders such as majordepressive disorder, anxiety disorder (e.g., general anxiety disorder,social anxiety disorder, panic disorder, obsessive compulsive disorder,etc.), substance and alcohol abuse, and attention-deficit hyperactivitydisorder (ADHD). Further, cardiovascular disease, stroke, hypertension,obesity (e.g., high body mass index (BMI)), cancer, female infertility,and metabolic disorders, such as type 2 diabetes, among others are alsohighly comorbid with certain eating disorders. Without being bound bytheory, it is possible that eating disorders share underlyingneuroendocrine, metabolic and other psychophysiological patterns withthese other disorders that either increase risk for the development ofan eating disorder or reduce treatment success and/or increase risk forthe development of these additional conditions.

A. Biophysical Characteristics of Individuals with Eating Disorders

Eating disorders belong to a mental disorder category encompassingcomplex and multifactorial disorders that are thought to be caused bymany contributing factors. The underlying neurobiological and metabolicmechanisms or etiology of eating disorders are uncertain and/or may varydepending on the category of eating disorder; however, evidence suggeststhat psychological, genomic and other biological risk factors arepresent in patients identified with eating disorders. Moreover,neurobiological heterogeneity in monoaminergic transmitter systems, thehypothalamic-pituitary-adrenal (HPA) axis, metabolic hormonal pathways,inflammatory mechanisms, and psychophysiological reactive and neuralcircuits have been demonstrated between individuals diagnosed witheating disorders and healthy individuals (Lechin, F., et al., DiabetesMetab Syndr Obes., 2010, 3: 311-317; Warren, M. P., J Clin EndocrinolMetab, 2011, 96: 333-343; Herpertz-Dahlmann, B., et al., Eur ChildAdolesc Psychiatry, 2017, 26: 1031-1041; Mayhew, A. J., et al.,Neuroendocrinology, 2018, 106: 292-306). In addition to differencesbetween individuals diagnosed with an eating disorder and healthyindividuals, those who do meet the criteria for a diagnosis of an eatingdisorder can vary in the severity of their symptoms as well as the typeof symptoms they experience.

Psychological stress, including chronic stress, can have deleteriouseffects on the brain's neural circuits as well as whole-bodyphysiological states, and is a crucial factor underlying mentaldisorders, with variation in stress susceptibility, responsivity andresilience providing variances in disorder presentation and severity(Halaris, A., Curr Topics Behav Neurosci, 2017, 31:45-70). Theneuro-hormonal systems that play a critical role in stress responses andhomeostasis include the HPA axis and noradrenergic systems. Thenoradrenergic system includes a dense network of axons that extend fromthe locus coeruleus in the brain stem throughout the brain including thehippocampus, amygdala, thalamus and hypothalamus, as well as projectionsthat extend down the brain stem to synapse with sympathetic nerve fibersin the thoracic region.

Correlative links have been implicated between a variety of mood andcognitive disorders and chronic or prolonged hyperactivity of thesympathetic branch of the autonomic nervous system. As shown in FIG. 1 ,the SNS is a branch of the autonomic nervous system along with theenteric nervous system and parasympathetic nervous system. The SNS isprimarily an involuntary bodily control system typically associated withstress responses. It is always active at a basal level (calledsympathetic tone) and becomes more active during times of stress. Fibersof the SNS extend through tissue in almost every organ system of thehuman body. For example, some fibers extend from the brain, intertwinealong the aorta, and branch out to various organs. As groups of fibersapproach specific organs, fibers particular to the organs can separatefrom the groups. The SNS regulates the function of virtually all humanorgan systems by localized release of catecholamines (e.g.,norepinephrine) from sympathetic nerve terminals innervating thesetissue and organ systems, spillover of norepinephrine from vascularneuro-muscular junctions (the primary source of norepinephrine inplasma), and by systemic circulation of catecholamines (e.g.,epinephrine, norepinephrine) released from the adrenal gland in responseto acute, transient stress or threats. Long-term variations in basallevels, increases in basal levels due to aging, as well as spikes ofcirculating catecholamines from hyperactivity of the SNS responding tolife circumstances can also exert more enduring regulatory effects ongene expression by altering constitutive gene expression profiles in awide variety of tissues and organ systems.

In addition to release of norepinephrine from sympathetic nerveterminals innervating these tissue and organ systems, perivascularadipose tissue, which closely surrounds most blood vessels (except inthe brain), has been shown to contain pools of norepinephrine. Renalperivascular adipose tissue, in particular, can release storednorepinephrine, thereby altering renal vascular function andcontributing to spillover of norepinephrine to plasma.

Once released, norepinephrine binds adrenergic receptors on peripheraltissues. In addition, activation (e.g., norepinephrine release) ofnoradrenergic nuclei in the central nervous system (CNS) can result fromtransmitted impulses from activated afferent renal sympathetic neurons.Binding to adrenergic receptors either in the periphery or in the CNScauses a neuronal and hormonal response. The physiologic manifestationsinclude pupil dilation, increased heart rate, occasional vomiting, andincreased blood pressure. Increased sweating is also seen due to bindingof cholinergic receptors of the sweat glands. It is known that long-termSNS hyperactivity has been identified as a major contributor to thecomplex pathophysiology of hypertension, states of volume overload (suchas heart failure), and progressive renal disease, both experimentallyand in humans. Moreover, correlative links between activation of the SNSand systemic inflammation, arterial stiffness, atherosclerosis,metabolic disorders, insulin resistance, and other cardiovascularconditions have been established. As mentioned above, many of theseconditions are comorbid with eating disorders.

Increased levels of catecholamine (e.g., norepinephrine) spillover andsecretion are associated with eating disorders. For example, higherlevels of circulating catecholamines, such as norepinephrine (in theperiphery and central nervous systems), have been reported in stress andfear-related disorders (e.g., anxiety disorders) as well as depressionwhich share common underlying etiology with eating disorders. Forexample, activated noradrenergic system is implicated in psychologicalstress, which is one of the primary risk factors for eating disorderdevelopment. Without being bound by theory, this suggests that increasedSNS activity is present in eating disorder patients.

Other indicators of increased SNS tone in patients with eating disordersinclude elevations in heart rate, blood pressure, skin conductance, andplatelet activation as well as a decrease in heart rate variability(e.g., a measure of beat-to-beat fluctuations in heart rate). Incontrast, healthy individuals that do not meet the criteria for aneating disorder may exhibit significantly lower plasma catecholaminelevels and may not display other indicators of elevated SNS activity.

Without being bound by theory, increased levels of norepinephrine canaccount for many aspects of eating disorder-associated symptoms,including, for example, intense fear of gaining weight or becoming fat,cognitive behaviors that interfere with weight gain (e.g., calorierestriction, purging, use of laxatives, etc.), preoccupation ordisturbance in the way one sees body weight or shape, eating largeamount of food in a discrete amount of time (e.g., within a 2 hourperiod), sense of lack of control over eating, eating untiluncomfortably full, eating large amounts of food when not feelingphysically hungry, recurrent compensatory behavior to prevent weightgain (e.g., self-induced vomiting, misuse of laxatives, diuretics, ormedications), fasting, excessive exercise, feeling ashamed or disgustedwith oneself, or depressed, impaired concentration, irritability, andfeelings of sadness or anxiousness. Hyperactive SNS activity in patientswith eating disorders would also present an on-going challenge totreatment success as levels of norepinephrine increase or spike inresponse to stressors and/or worsening psychological stress in theseindividuals.

Individuals with eating disorders also exhibit altered HPA axis functionsuch as having elevated levels of corticotropin-releasing hormone (CRH)and increased nocturnal CRH activity, which initiates stimulation of theHPA axis in response to stress (e.g., psychological stress, etc.).Hyperactivity of the HPA axis as well as higher circulating cortisol(i.e., glucocorticoid) levels compared to healthy controls (e.g.,patients without eating disorders) also exemplify HPA axis dysfunctionin remitted as well as currently diagnosed patients. Decreasedresponsiveness to glucocorticoids (e.g., glucocorticoid resistance) andsubsequent HPA axis dysfunction is a hallmark of major depression(Miller, A. H., et al., Biol Psychiatry, 2009, 65: 732-741), and mayalso be in related disorders (e.g., eating disorders, anxietydisorders). Alterations to HPA axis function, both reflecting a currentmood state as well as long lasting changes to brain function, may bemediated, in part, by alterations in the glucocorticoid receptor. Inparticular, it has been demonstrated that patients with depression andanxiety disorders exhibit reduced glucocorticoid sensitivity,preferential expression of a dominate negative form (GR-β) of theglucocorticoid receptor, and increased levels of FKBP5, which is aco-chaperone of the glucocorticoid receptor that inhibits ligand bindingand pathway activation (Menke, A., et al., Genes, Brain and Behav, 2013,12: 289-296; Spijker, A. T. and van Rossum, E. F. C.,Neuroendocrinology, 2012, 95:179-186; Miller, A. H., et al., BiolPsychiatry, 2009, 65: 732-741). Without being bound by a theory, anindividual's level of chronic exposure to stress, and thereby cortisolexposure, in brain regions associated with emotion and cognition (e.g.,the limbic system), may be important in the development or prediction offuture risk of an eating disorder in the individual, and this additionalmajor stress response system may determine longer-term patterns ofstress responses in eating disorder patients.

CRH and norepinephrine are known to interact in regions of the braininvolved in stress responses to increase fear conditioning, interfere inemotional response, cognition and encoding of emotional memories(Jedema, H. P. and Grace, A. A., J Neurosci, 2004, 24:9703-9713).Further reinforcing a prolonged psychological stress response and thepathophysiology of eating disorders, CRH is elevated in the locuscoeruleus of eating disorder patients and has been shown to activateneurons in the locus coeruleus which would result in increasednorepinephrine levels throughout the CNS.

Neuropeptide Y (NPY), a 36-amino-acid peptide transmitter that isexpressed in brain regions that regulate stress and emotional behaviors,has shown to buffer stress responses and promote increased ability tocope with emotional trauma (Enman, N. M., et al., Neurobiol Stress,2015, 1: 33-43; Sah, R. and Geracioti, T. D., Mol Psychiatry, 2013,18:646-655). In particular, central nervous system NPY concentrationlevels may normally control or suppress pro-stress transmitters such asCRH and norepinephrine in the brain (Id.). However, both central andperipheral nervous system NPY concentrations are significantly lower inindividuals with anxiety-related and mood disorders when compared tohealthy controls (Id.), possibly attenuating the individuals' resilienceand coping ability in response to psychological stress. Without beingbound by theory, and since NPY functions to inhibit CRH andnorepinephrine promotion of stress and fear responses, as well asreduces the release of norepinephrine from sympathetic neurons,decreased NPY activity may contribute to SNS hyperactivity in patientswith eating disorders.

An additional physiological characteristic associated with an eatingdisorder includes a pro-inflammatory state, including chronicinflammation. For example, elevated levels of inflammatory cytokines,such as interleukin-6 (IL-6), IL-8, tumor necrosis factor-alpha (TNF-α)as well as other inflammatory markers, such as C-reactive protein (CRP),are elevated in individuals with mental disorders, and peripheral levelsof these inflammatory markers correlate positively with eating disordersymptomology (e.g., anxiety, obsessive compulsive behavior, fatigue,cognitive dysfunction, impaired sleep). Moreover, higher levels ofinflammatory biomarkers are associated with exacerbated eating disordersymptoms, and without being bound by theory, may pose an increased riskin the development of an eating disorder.

Mental disorders are also associated with increased activation of thetranscriptional factor, nuclear factor-κB (NF-κB), which is activated byexposure to psychosocial stress and sympathetic nervous system outflowpathways, and is responsible for cytokine production. Cytokine-inducedincreases in neural activity in brain regions, such as the anteriorcingulated cortex and the basal ganglia, have been associated thedevelopment of mood and anxiety symptoms, and are associated withalterations in brain neurotransmitter metabolism (e.g., serotonin,norepinephrine and dopamine), neuroendocrine function and neuralplasticity (Id.). For example, cytokine-induced immune responses haveshown to increase the number of reuptake pumps, thereby decreasingneurotransmitter availability, and shunting tryptophan away from theproduction of serotonin in the brain. Without being bound by theory,increased SNS activity coupled with reduced sensitivity to theanti-inflammatory effects of glucocorticoids (e.g., due toglucocorticoid resistance) as a result of chronic psychological stress,both contribute to chronic activation of inflammatory responses.

Currently prescribed treatment plans for patients diagnosed with eatingdisorders typically consist of psychotherapy, physical interventionand/or pharmaceutical drugs. Conventional drug therapies may beadministered to address particular symptoms associated with eatingdisorders in attempts to lessen those particular symptoms. For example,anti-anxiety medication (e.g., benzodiazepines, buspirone, β-blocker,etc.), antidepressants (e.g., selective serotonin reuptake inhibitors(SSRIs) that raise the level of serotonin in the brain, tricyclicantidepressants, monoamine oxidase inhibitors (MAOIs), etc.),anti-psychotic drugs, anti-hypertensive drugs, mood stabilizers, etc.,may provide mild to moderate and/or temporary relief from eatingdisorder symptoms, anxiety-related symptoms, cognitive and/or memorydifficulties, etc. However, most patients do not get adequate treatmentand for many patients, medications are ineffective. Moreover, drugadherence over several years or decades in a manner than maintains sleepquality, mood, anxiety disorder-related symptoms, blood pressure, etc.,remains a challenge for most patients. For many patients, improvementsmay not be apparent until after up to 4 or more weeks of drug treatment,causing delays in ascertaining whether the prescribed drug or drugcombination is suitable for the particular patient. Furthermore, somemedications do not work or stop working effectively over time, and somebecome addictive and/or cause other intolerable side effects. Additionaldrawbacks to use of drugs for treating a patient with an eating disorderinclude the possibilities of adverse reactions associated with thesemedications (e.g., heart failure, hypotension, bradycardia, severedepressive episodes, suicide ideation, sexual dysfunction, weight gainor unhealthy weight loss, death, etc.), as well as other undesirableside-effects, on a patient-by-patient basis.

Additionally, pharmaceutical intervention for other contributors andrisk factors associated with eating disorders further complicates drugadministration and management of contraindications betweenanti-inflammatory medications, anti-hypertensive drugs, anti-anxietydrugs, antidepressant drugs, mood stabilizers among others administeredto support patients with eating disorders, and adherence over yearsremains a challenge. Various psychotherapy treatments can be prescribedin combination with a medication plan or as a stand-alone treatment.While psychotherapy (e.g., cognitive-behavioral therapy, interpersonaltherapy, etc.) may provide some patients with skills in new ways ofthinking and behaving, it may not be effective for more severe forms ofeating disorders such as anorexia, bulimia, and binge eating, amongothers. Some patients with severe or medication adverse and/or resistantdisorders may be treated with several sessions of electroconvulsivetherapy, phototherapy, deep brain stimulation and others with mixedresults. Various aspects of the present technology address SNS effectson risk factors associated with eating disorders while overcoming thesechallenges.

B. Risk Factors Associated with Development of Eating Disorders and/orRelated Conditions

As discussed above, eating disorders are psychophysiological disordersencompassing dysregulation of complex neuro- and hormonal-biochemicalpathways that are known to be caused by many contributing factors. Whilemany biomarkers distinguishing patients with an eating disorder andhealthy individuals demonstrate heterogeneity following pathogenesis inan individual, certain earlier-identifiable conditions as well asgenetic and/or biophysical variances in a patient are recognized asbeing either contributory factors and/or predictors of a likelihood thata patient will develop an eating disorder or, in the case of remittedpatients, a likelihood that the patient will redevelop the same eatingdisorder or develop a different eating disorder. In particular, manyunderlying conditions, genetic variances and other abnormalitiesdetectable in individuals either prior to the development of an eatingdisorder or during remittance, may affect the likelihood of theindividual subsequently developing one or more eating disorders. Suchunderlying conditions and genetic/biophysical variances constituteeating disorder predictors or risk factors.

As discussed above, some identified risk factors for increasing alikelihood of developing an eating disorder include certain demographicvariables such as, for example, female gender, drug or alcohol abuse,and being physically inactive. Additionally, it has been shown that ifthe patient has a history of eating disorders, mental illness, has afamily history of eating disorders, depression or other mental illness,has experienced one or more adverse life events (e.g., illness, abuse,loss of a loved one, unemployment, psychological trauma, etc.), has oris experiencing a difficult relationship, has experienced priortraumatic events, has had an adverse childhood experience, is currentlyin a stressful situation, has or is experiencing a major life change, orhas or is experiencing an extended period of stress (e.g., chronicstress), among others, the patient has an increased likelihood ofdeveloping an eating disorder.

Without being bound by theory, increased SNS activity in the patient asa result of psychological and/or other forms of chronic stress canpredispose the individual to developing an eating disorder. For example,chronic stress has been shown to alter neural circuits and structures inthe brain (e.g., hippocampus, prefrontal cortex, etc.) (Pitman, R. K.,et al., Nat Rev Neurosci., 2012, 13: 769-787) that may increase theindividual's sensitivity to contextual threat. Such sensitization of theSNS may be responsible for higher heart rates during a subsequentexposure to a trigger, stressful situation or a traumatic event, whichmay be a predictive risk for future development of a mood disorderaccompanied by an eating disorder. Moreover, lower heart ratevariability characterizes eating disorders and may also be predictive ofeating disorder development. In certain embodiments, prior exposure totrauma (e.g., childhood abuse, prior sexual abuse, prior combatexperience, etc.) may increase the individual's sensitization of theSNS, thereby lowering the threshold barriers for the development of aneating disorder.

While there is evidence for the presence of SNS hyperactivity inpatients presenting with an eating disorder, there is further evidencethat a strong adrenergic response to a traumatic event or other adverselife circumstance may mediate or in part contribute to the developmentof an eating disorder in certain individuals. Some biochemicalinducements of the increase in norepinephrine release in response to SNSactivation include genetic and/or other inhibition paths that lower NPYlevels, as well as lower numbers or affinity of α2-adrenergic receptors(Pitman, R. K., et al., Nat Rev Neurosci., 2012, 13: 769-787; Sherin, J.E., et al., Dialogues Clin Neurosci, 2011, 13: 263-278). Additionally,there is evidence that a pro-inflammatory state (e.g., as indicated byincreased levels of inflammatory cytokines) may increase risk orvulnerability for development of an eating disorder particularly whenpatients present with chronic stress. For example, it has been shownthat increased levels of CRP (e.g., greater than about 3 mg/L; greaterthan about 5 mg/L; etc.) were predictive of psychological distress anddepression, and without being bound by theory, elevated levels of CRPcan present as an additional risk factor that can establish a predictiverisk for the development of an eating disorder.

Correlative links between activation of the SNS and high blood pressure,coronary heart disease, stroke, systemic inflammation, arterialstiffness, endothelium dysfunction, atherosclerosis, metabolicdisorders, insulin resistance, end organ damage, obesity (e.g., highbody mass index (BMI)), and other cardiovascular conditions have alsobeen established. As discussed above, these conditions/diseases havefurther been shown to be correlative with an incidence ofanxiety-related disorders and various eating disorders. As such, it isposited that these conditions/diseases, which are indicative of chronicactivation of SNS, present as risk factors that can establish apredictive risk for the development of an eating disorder. In fact,anxiety disorders and other mood disorders are more prevalent in peoplewho have suffered a major cardiac event. Strokes (e.g., acute ischemicstroke, lacunar stroke, transient ischemic attack (TIA), hemorrhagicstroke, etc.) are also highly associated with the development of mentaldisorders (e.g., anxiety, depression), and post-stroke mental disordersare associated with increased morbidity and mortality in such patients.

Additionally, with respect to blood pressure regulation, the nocturnalblood pressure of healthy individuals drops or “dips” more than 10% ofthe average daytime blood pressure value, which is followed by anincrease in blood pressure with arousal from sleep, known as the morningsurge in blood pressure (MSBP). In contrast, “elevated,” i.e. limiteddrops in blood pressure during the nighttime (e.g., nighttime bloodpressure reduction that is less than 10% of average daytime bloodpressure) as well as excessive surge in MSBP (e.g., early morninghours), is associated with an increased risk of cardiovascular eventsand strokes even in normotensive patients (FitzGerald, L., et al., J HumHypertens, 2012, 26: 228-235; Kario, K. and Hamasaki, H., J ClinHypertens, 2015, 17: 682-685). Several mental and mood disorderscorrelate with higher MSBP and the increase in MSBP is proportional tothe severity of the disorder-related symptoms and is irrespective of“dipping” status (Id.). Men and older populations of patients furtherdemonstrate “non-dipping” nocturnal blood pressure which is furtherassociated with more sleep-related symptoms and poorer overall sleepquality as well as increased risk in cardiovascular events (Id.).Psychological risk factors, such as depression and anxiety, are reportedto influence cardiovascular events and to impact hypertension, andexcessive MSBP and/or “non-dipping” nocturnal blood pressure may be riskfactors for the development and/or the severity for hypertension,cardiovascular disease and stroke. Moreover, excessive MSBP and/or“non-dipping” nocturnal blood pressure may be risk factors for thedevelopment or progression of eating disorders in such patients.

In addition to chronic and/or acute SNS hyperactivity, increasedglucocorticoid (e.g., cortisol) levels, and HPA axis dysfunction, e.g.,as a measurement of basal cortisol levels in response to awakening as anindicator for endogenous stress response, provide additional riskfactors that can be considered in establishing a predictive riskassessment for the development of an eating disorder in a patient. Forexample, and without being bound by theory, an abnormally highmeasurement of cortisol awakening rise (CAR), which reflects the naturalresponse to awakening with a normal/natural increase in cortisol levels,may not only be characteristic of patients with an mental and mooddisorders, but can be predictive for developing an eating disorder, andthereby provides an additional risk factor of subsequent eating disorderdevelopment. Without being bound by theory, it is thought that highlevels of cortisol resulting in glucocorticoid resistance and increasedHPA axis activity fails to inhibit CRH/norepinephrine responses tostress and further exacerbates cognitive dysfunction (e.g., memorydeficits, inability to concentrate) and eating disorder-related symptomsin these individuals.

In addition to predisposition factors associated with activation of theSNS and other demographic risk factors, certain genetic variations amongindividuals have also been shown to be predictive risk factors for thedevelopment of mental and mood disorders. Some of these genetic riskfactors are common to both major depressive disorder, anxiety disorderand eating disorders. For example, genes that affect risk fordevelopment of an eating disorder may also influence risk for otherpsychiatric disorders and vice versa. As with other mental disorders,influences on eating-related disorders are likely polygenic; at least 17single nucleotide polymorphisms (SNPs) in 15 different genomic regionshave been associated with depression and related psychiatric disordersin at least one published study (Hyde, C. L., et al., Nature Genet,2016, 48: 1031-1036). These and other genetic variants demonstrated toinfluence risk for anxiety, depression, and associated eatingdisturbance symptoms include genes involved in HPA axis regulation, thelocus coeruleus/noradrenergic system, dopaminergic and serotonergicsystems (e.g., regulation of synapses, monoamine metabolism, etc.) andother neurodevelopment programs (Hyde, C. L., et al., Nature Genet,2016, 48: 1031-1036; Converge Consortium, Nature, 2015, 523: 588-591;Miller, A. H., et al., Biol Psychiatry, 2009, 65: 732-741).

With respect to HPA axis regulation, several known genetic variations inthe glucocorticoid receptor gene, NR3C1, affect glucocorticoidsensitivity (Spijker, A. T. and van Rossum, E. F. C.,Neuroendocrinology, 2012, 95:179-186). For example, the ER22/23EKpolymorphism, which is associated with mild glucocorticoid resistance,and the BclI polymorphism, which is associated with increased stabilityof the mRNA of the dominant negative GR-β isoform, are both associatedwith a higher risk of developing a mood and related disorders (Id.).Additionally, carriers of particular heritable polymorphisms in thegenes encoding for FK506-binding protein 5 (FKBP5; co-chaperone of theglucocorticoid receptor that inhibits ligand binding and pathwayactivation) leading to increased intracellular FKBP5 protein expression,the CRH receptor 1 (CRHR1 rs242939 polymorphism), and serotonintransporter (SLC6A4; responsible for serotonin transport and reuptake)have been shown to be overrepresented in patients with depression, andcarriers of these genetic variants may have an increased likelihood ofdeveloping some types of eating disorders (Mahan, A. L. and Ressler, K.J., Trends Neurosci, 2012, 35: 24-35; Pitman, R. K., et al., Nat RevNeurosci., 2012, 13: 769-787; Spijker, A. T. and van Rossum, E. F. C.,Neuroendocrinology, 2012, 95:179-186; Miller, A. H., et al., BiolPsychiatry, 2009, 65: 732-741).

Further evidence has suggested that in addition to genotype, epigeneticfactors such as gene methylation, histone deacetylation, and other geneexpression differences can influence or accompany the development ofeating and other mental disorders, and these genetic profiles can bescreened to determine patients presenting certain geneticpre-dispositions associated with high or increased risk of developing aneating disorder (Spijker, A. T. and van Rossum, E. F. C.,Neuroendocrinology, 2012, 95: 179-186; Mahan, A. L. and Ressler, K. J.,Trends Neurosci, 2012, 35: 24-35; Pitman, R. K., et al., Nat RevNeurosci., 2012, 13: 769-787).

Once a clinical eating disorder is present, a host of physiologicalchanges occur in the patient, including SNS and immune systemactivation/hyperactivation, neuroendocrine changes, rhythm disturbances,oxidative stress, platelet hypercoagulability and endothelialdysfunction, all of which exert a negative impact on cardiovascularhealth. As discussed above, eating and other mental disorders arecharacterized by, among other things, elevated SNS activity, reducedheart rate variability, increased plasma cortisol levels and elevatedinflammatory responses, all of which are associated with increased riskof cardiovascular disease (Brown, A. D., et al., CNS Drugs, 2009,23:583-602). In particular, psychological stress accompanying an eatingdisorder causes dysregulation of the SNS and the HPA axis which canprecipitate numerous downstream physiological effects throughout thebody, including hypertension, left ventricular hypertrophy, coronaryvasoconstriction, endothelial dysfunction, platelet activation and theproduction of pro-inflammatory cytokines, all of which carry an elevatedrisk of ventricular arrhythmias and myocardial infarction (MI).Additionally, eating disorders have been shown to be associated withincreased morbidity and mortality in patients having cardiovasculardisease and/or precipitate heart failure (e.g., anorexia). Without beingbound by theory, mental stress (which accompanies and/or at leastpartially precipitates eating disorders) has been shown to activatecardiac sympathetic nerves with downstream effects of heart rhythmdisturbances, increased risk of ventricular arrhythmias, decreased bloodflow, left ventricular hypertrophy, MI and sudden death. Furthermore,essential hypertension can be triggered by and maintained by chronicpsychological stress. Accordingly, eating disorders are a risk factorfor the development of cardiovascular disease and stroke, with therelative risk level proportional to the severity of disorder in thepatient. Furthermore, eating disorders in patients may increase futurerisk of stroke and transient ischemic attacks (TIAs). Excess stroke andTIA risk associated with eating disorders may stem from activation ofthe HPA axis, elevated catecholamines, and elevated inflammatoryresponses (e.g., increased CRP, IL-6, etc.) which are all related tostroke risk.

C. Identification of Patients or Cohorts Diagnosed with an EatingDisorder or at Risk of Developing an Eating Disorder

Patients presenting with a high likelihood of having an eating disordercan include patients presenting with one or more of (1) eating disordersymptoms (e.g., intense fear of gaining weight or becoming fat,behaviors that interfere with weight gain (e.g., calorie restriction,purging, use of laxatives, etc.), disturbance in the way one sees bodyweight or shape, eating large amount of food in a discrete amount oftime (e.g., within a 2 hour period), sense of lack of control overeating, eating until uncomfortably full, eating large amounts of foodwhen not feeling physically hungry, recurrent compensatory behavior toprevent weight gain (e.g., self-induced vomiting, misuse of laxatives,diuretics, or medications), fasting, excessive exercise, feeling ashamedor disgusted with oneself, or depressed, etc.), (2) family history ofdepression, anxiety disorder or other mental illness, (3) priordiagnosis of an acute or chronic stress disorder, (4) prior diagnosis ofany mood disorder (e.g., depression, anxiety, bipolar, sleep disorder,etc.), and/or (5) depression symptoms (e.g., depressed mood for most ofthe day, anhedonia, psychomotor agitation or retardation nearly everyday, anergia, poor appetite or overeating, low self-esteem or feelingsof worthlessness, changes in cognitive ability, and/or negative feelingsabout self or the world). Patients demonstrating certain risk factors oreating disorder symptoms may also have an increased likelihood of havingan eating disorder if they exhibit with one or more of elevated SNSactivity (e.g., catecholamines detected in urine or plasma), low centralnervous system NPY levels, elevated cortisol levels, glucocorticoidresistance (e.g., as assessed via dexamethasone suppression test),elevated CAR, low heart rate variability, elevated MSBP, limited or no“dipping” of nocturnal blood pressure, elevated levels of seruminflammatory cytokine levels (e.g., IL-6, IL-8, TNF-α, CRP, etc.),and/or endothelial dysfunction.

Some patients may also present with comorbid conditions or diseases suchas cardiovascular disease, having suffered a major cardiac event (e.g.,MI, coronary artery bypass surgery), having had a stroke or risk ofstroke, hypertension or pre-hypertension, ventricular arrhythmias, leftventricular hypertrophy, above-normal cholesterol levels,atherosclerosis, insulin resistance or other metabolic disorder,arterial stiffening or aneurysm(s), obesity or being overweight (e.g.,high BMI), cancer, and/or patients with active substance abuse, ahistory of substance abuse, or prior mental disorder. In certainembodiments, the patient can present with one or more risk factorsand/or comorbid conditions associated with an increased likelihood ofhaving an eating disorder. However, in other embodiments, suchassociated conditions may not be present in a patient having an eatingdisorder and/or at risk of developing an eating disorder. For example,the patient may be normotensive, have no evidence of cardiovasculardisease, normal BMI, normal insulin sensitivity, and/or no elevatedlevels of inflammatory biomarkers.

Patients presenting with a high or increased risk of developing aneating disorder can include patients having one or more demographic orbiophysical risk factors as described herein and who have not met thediagnosis standard as set forth in DSM-5 and/or patients in which one ormore eating disorder screening tools or instruments used to give aprofessionally-accepted diagnosis have not confirmed an eating disorder.However, such patients may present one or more risk factors associatedwith an increased likelihood of developing an eating disorder. Forexample, the patient may have an increased likelihood of a presentcondition progressing toward an eating disorder, such as a patientpresenting some but not a qualifying number of symptoms on the DSM-5, orin another embodiment, a patient may present a qualifying number ofsymptoms but has not experienced a threshold level of severity for oneor more of those symptoms. In another example, the patient maydemonstrate a combination of described risk factors (e.g., elevated SNStone, high CAR, glucocorticoid resistance, elevated levels of CRP, lowlevels of central NPY, having experienced depressive episodes and/oranxiety attacks, history of child abuse or trauma, and/or family historyof anxiety disorder, depression and/or other mental illness, etc.) andcurrently be experiencing chronic and/or excessive psychological stress(e.g., experiencing major life change, a difficult relationship, illnessor disease of self or loved one, death of loved one, occupationalstress, etc.).

In particular embodiments, patients having an increased risk ofdeveloping a moderate or severe eating disorder may have, for example,mild or acute eating disorder symptoms and demonstrate one or more ofthe following risk factors: (1) previously experienced traumatic eventsor experiences, (2) personal history of an eating disorder, (3) familyhistory of depression, anxiety disorder or other mental illness, (4)prior diagnosis of acute stress disorder, (5) prior diagnosis of anymood disorder (e.g., depression, anxiety, bipolar, panic disorder,etc.), and/or (6) depression symptoms (e.g., depressed mood for most ofthe day, anhedonia, psychomotor agitation or retardation nearly everyday, anergia, poor appetite or overeating, low self-esteem or feelingsof worthlessness, changes in cognitive ability, and/or negative feelingsabout self or the world). Further risk factors for the development of aneating disorder in patients can include physiological markers such aselevated SNS activity (e.g., increased levels of catecholamines asdetected in urine or plasma), elevated cortisol levels, low centralnervous system NPY levels, glucocorticoid resistance (e.g., as assessedvia dexamethasone suppression test), elevated CAR, low heart ratevariability, elevated MSBP, limited or no “dipping” of nocturnal bloodpressure, low baroreceptor sensitivity (e.g., an assessment ofcardiovascular autonomic neuropathy), and/or elevated levels of seruminflammatory cytokine levels. A patient at-risk of developing an eatingdisorder may be hypertensive or pre-hypertensive and/or show elevatedSNS tone in the form of blood pressure dysregulation (e.g., elevated24-hour blood pressure variability). However, in many instances,patients having an eating disorder or being at-risk of developing aneating disorder can have normal blood pressure levels (e.g., do not havehypertension or pre-hypertension).

In some embodiments of the present technology, the patient can have acalculated risk score for (i) determining an eating disorder status(e.g., diagnosis, severity, etc.) or (ii) the prediction of developingan eating disorder that is above a threshold eating disorder risk score.Such a calculated eating disorder risk score can indicate a likelihoodof an eating disorder diagnosis or, in another embodiment, a likelihoodof developing an eating disorder. In one embodiment, for example, acalculated eating disorder risk score for determining an eating disorderstatus can be based upon one or more data sets known in the art. Forexample, an eating disorder risk score based upon the Eating DisorderExamination Questionnaire (EDE-Q). The EDE-Q, among other assessmenttools, can be used to establish an eating disorder risk score fordetermining an eating disorder status (e.g., diagnosis/severity), andcan be based upon an analysis of the patient's assessment acrossmultiple possible risk factors. For example, the patient can be queriedand assessed for core eating disorder symptoms indicated in the DSM-5and the International Statistical Classification of Diseases and RelatedHealth Problems (ICD-10) classification systems to determine if apatient has a mild, moderate, or severe eating disorder. One of ordinaryskill in the art will recognize that the EDE-Q scale study is only onestudy in which a risk score calculation can be developed and applied.Other published data sources documenting multiple possible risk factorsand corresponding scores may use any of many well described techniques.Such techniques for developing tools to calculate an eating disorderrisk score could be empirical, based on multivariate regression, orusing artificial intelligence (e.g. Bayesian probability, machinelearning, etc.) among other techniques known in the art.

In other embodiments, a patient presenting a high or increased risk ofdeveloping an eating disorder can have a genetic disorder or determinedgenetic pre-disposition to developing an eating or other associatedmental disorder. For example, specific forms (e.g., polymorphisms) ofthe glucocorticoid receptor gene, NR3C1, affect glucocorticoidsensitivity and additional polymorphisms in the gene known as FKBP5, aco-chaperone of the glucocorticoid receptor, is associated withincreased glucocorticoid resistance and increased risk foranxiety-related disorders. Additionally, carriers of polymorphisms inthe genes encoding for the CRH receptor 1 are associated with anincreased likelihood of developing a mood disorder. As evidence hassuggested that genotype, gene methylation, histone deacetylation, andgene expression differences among other epigenetic factors, influence oraccompany the development of eating disorders, these genetic profilescan be screened to determine patients presenting certain geneticpre-dispositions associated with high or increased risk of developing aneating disorder.

A patient suspected of having an eating disorder can be evaluated for alevel of dysfunction or severity of symptoms and/or sequelae associatedwith eating disorders. Evaluation of core symptoms (e.g., intense fearof gaining weight or becoming fat, behaviors that interfere with weightgain (e.g., calorie restriction, purging, use of laxatives, etc.),disturbance in the way one sees body weight or shape, eating largeamount of food in a discrete amount of time (e.g., within a 2 hourperiod), sense of lack of control over eating, eating untiluncomfortably full, eating large amounts of food when not feelingphysically hungry, recurrent compensatory behavior to prevent weightgain (e.g., self-induced vomiting, misuse of laxatives, diuretics, ormedications), fasting, excessive exercise, feeling ashamed or disgustedwith oneself, or depressed, etc.), can include a self-reporting orassessment of changes from a person's usual level of function (e.g.,prior to on-set of symptoms) to a current condition. Evaluation inputmay also come from trusted sources (e.g., trusted family members,friends, primary physician, etc.) that can provide information onchanges in performance on daily activities, job/employment performance,behavior or mood changes, sleep patterns, as well as angry outbursts,irritability or aggression and/or other risky or destructive behaviors,etc.

Physicians or other qualified clinicians may also administer one or morequestionnaires or diagnostic tests, such as screening tools, to assesseating disorder risk, severity and diagnosis. Eating disorder screeningtools such as the EDE-Q, as well as other screening instruments thatlook at multiple risk factors for predicting the patient-specificclinical features along with eating disorder status can be utilized inthe assessment process. One of ordinary skill in the art will recognizeother eating disorder tests and scales that can be used to determine thestatus of an eating di of a patient. In some embodiments, for example, apatient may be suspected of having an eating disorder based upon asingle test score or outcome, combined test scores from multiple tests,or one or more test scores from multiple tests. Diagnosis can be madebased upon, for example, meeting or exceeding a threshold test score. Inother embodiments, a patient may demonstrate an increase in symptomseverity as reflected in test scores taken over time. For example, aparticular patient may show an increase in eating disorder risk via aresult in a test score between taking tests two weeks after on-set ofsymptoms, one month after on-set of symptoms, six months after on-set ofsymptoms, and a year or more after on-set of symptoms. Cognitivefunctioning (e.g., cerebral activities encompassing reasoning, memory,attention, and language), emotional/social functioning (e.g., traits andabilities involving positive and negative aspects of social andemotional life like empathy, interpreting emotion, speed and intensityof emotion generation, and efficacy of coping with negative emotions,etc.), and sleep dysfunction-associated symptoms, as well as other datathat can be collected in an evaluation of a patient, are based onself-report, observational (behavioral), or psychological data.

In a particular example, if a patient could respond (or a cliniciancould so indicate with respect to a patient) in affirmation (i.e.,answering “yes”) and/or if the a patient can indicate at least amoderate level of severity to one or more of the following statements,then the patient could be diagnosed with an eating disorder and, in someembodiments, be treated with renal neuromodulation to treat the eatingdisorder: Over the past month, and at a frequency of less than once aweek, once or twice a week, or three or more times a week—

-   -   a) you deliberately try limiting the amount of food you eat,    -   b) you have gone for long periods of time without eating        anything,    -   c) you have tried to exclude from your diet foods that you like,    -   d) you have a definite desire to have an empty stomach,    -   e) you have a definite desire to have a totally flat stomach,    -   f) thinking about food, eating or calories makes it difficult        concentrate,    -   g) thinking about shape or weight of your body makes it        difficult to concentrate,    -   h) you have a definite fear of losing control over eating,    -   i) you have a definite fear that you might gain weight,    -   j) you have felt fat, and    -   k) you have a strong desire to lose weight,

Additional screening tools or eating disorder risk score calculatingtools may ask additional questions to identify the presence or absenceof known eating disorder risk factors. For example, a patient may beasked to respond to one or more of the following questions in anassessment:

-   -   Do you have any medical conditions?    -   Have you lost interest in hobbies or activities?    -   Do you feel sad, irritable, or hopeless?    -   Do you feel nervous or worried?    -   Do you think something is wrong with your body?    -   Do you have a personal or family history of an eating disorder        or mental illness?    -   How many adverse life events (e.g., major illness, abuse, loss        of a loved one, unemployment, psychological trauma, etc.) have        you experienced that has caused you either high levels of stress        or chronic (e.g., greater than one year) stress?    -   Did you experience traumatic life events and/or abuse as a child        or adolescent?

Physicians or other qualified clinicians may also administer one or morequestionnaires or diagnostic tests, such as screening tools, to assessdepression symptoms that may accompany core eating disorder symptoms.For example, the Patient Health Questionnaire (PHQ-2) scale is atwo-item depression screener as exemplified in the following questions:

-   -   1. Have you ever had a period of two weeks or longer when you        were feeling depressed or down most of the day or nearly every        day?    -   2. Have you ever had a period of two weeks or longer when you        were uninterested in most things or unable to enjoy things you        used to do?

A patient having eating disorder symptoms and one or more depressionsymptoms can be a candidate for renal neuromodulation.

In addition to self-reporting, observational, or other psychologicaldata, a patient may also be evaluated for physiological data.Accordingly, a patient may demonstrate one or more physiologicalparameters associated with an eating disorder or, in other embodiments,with chronic psychological stress. Non-limiting examples ofeating-associated physiological parameters may include low heart ratevariability (e.g., as assessed by Standard Deviation NN intervals(SDNN)), decreased baroreceptor sensitivity (as an assessment ofcardiovascular autonomic neuropathy), heightened heart rate responses tostimuli/stress (e.g., via Stroop Color Test or Cold Pressor Test),elevated muscle sympathetic nerve activity (MSNA; a marker of SNSactivity), elevated systolic blood pressure, increased MSBP, lack of orlow levels of nocturnal blood pressure “dipping”, higher skinconductance (e.g., a measure of sweat activity thought to be under SNSinfluence), higher resting heart rate, disrupted sleep patterns or lowquality sleep, elevated peripheral inflammatory markers (e.g., IL-6,IL-8, CRP, TNF-α, etc.), low NPY levels (e.g., in the CNS and plasma),and other measures of sympathetic activity (e.g., increased renal and/ortotal body norepinephrine spillover, increased plasma norepinephrinelevels, increased urine levels of norepinephrine and metabolitesthereof, etc.). Further physiological parameters that can be riskfactors for an eating disorder may include increased cortisol levels,glucocorticoid resistance (e.g., as assessed via dexamethasonesuppression test), previous traumatic brain injury (TBI), and/ordecreased levels of neurotransmitter receptors (e.g., GABA,5-HT/serotonin, dopamine) in the brain (e.g., as assessed viaadministered radioligands followed by positron emission tomography(PET)).

In accordance with aspects of the present technology, patientspresenting with one or more risk factors for having an eating disorder,having a calculated eating disorder risk score, and/or one or more riskfactors for developing an eating disorder can be candidates fortreatment for an eating disorder. In other embodiments, some patientsmay also be candidates for renal neuromodulation for the prevention ofdeveloping an eating disorder in the patient. As noted above, renalneuromodulation is expected to efficaciously treat an eating disorderincluding one or more symptoms associated with an eating disorder. Renalneuromodulation is also expected to efficaciously prevent an incidenceof, reduce a severity of, or slow a progression of an eating disorder.Renal neuromodulation is further expected to improve a patient'scalculated eating disorder risk score correlating to an eating disorderstatus/diagnosis.

In certain embodiments, for example, renal neuromodulation treatsseveral clinical conditions characterized by increased overallsympathetic activity and, in particular, conditions associated withcentral sympathetic overstimulation such as pre-hypertension,hypertension, blood pressure variability, heart rate variability,vascular disease (e.g., vessel stiffening), metabolic syndrome, insulinresistance, diabetes, cancer, cognitive impairment (e.g., which canprogress to dementia), systemic inflammation, depression, and anxietydisorder, among others, that may be associated with and/or contribute toa severity or progression of an eating disorder in a patient. Thereduction of afferent neural signals typically contribute to thesystemic reduction of sympathetic tone/drive, and renal neuromodulationis expected to be useful in treating several conditions associated withsystemic sympathetic overactivity or hyperactivity. For example, and inaccordance with other aspects of the present technology, patientspresenting with one or more risk factors for having an eating disorderand/or having a positive clinical diagnosis for an eating disorder canbe candidates for renal neuromodulation treatment for preventing,reducing an incidence of, and/or reducing a severity of a cardiovascularcondition (e.g., coronary heart disease, MI, left ventricularhypertrophy, ventricular arrhythmias, etc.) and/or stroke (e.g., acuteischemic stroke, lacunar stroke, transient ischemic attack (TIA),hemorrhagic stroke, etc.) in the patient. In other embodiments, treatingpatients having an eating disorder in younger (e.g., 18-40 years of age)or in middle-aged (e.g., 40-65 years of age) patients may reduce anincidence of or improve an outcome of many comorbid conditions anddiseases including, but not limited to, cardiovascular disease, stroke,metabolic disorders, diabetes, elevated cholesterol, obesity, cancer,dementia, etc. Accordingly, in particular examples, patients having orat risk of having an eating disorder and who are suitable candidates fortreatment via renal neuromodulation can be between the ages of 18 and45, between the ages of 18 and 30, between the ages of 20 and 40, orbetween the ages of 20 and 35. In other embodiments, the patients may bebetween the ages of 35 and 65, between the ages of 45 and 65, betweenthe ages of 50 and 70, or the patient can be at least 35 years old, orat least 18 years old.

II. RENAL NEUROMODULATION FOR TREATING EATING DISORDERS AND/OR REDUCINGA RISK ASSOCIATED WITH THE DEVELOPMENT OF AN EATING DISORDER

Therapeutically-effective renal neuromodulation can be used for thetreatment of an eating disorder or for the treatment of one or moresymptoms and/or sequelae associated with an eating disorder, themanagement of an eating disorder, or to reduce an incidence of an eatingdisorder in patients identified as having a risk of developing an eatingdisorder at a future time. In further embodiments,therapeutically-effective renal neuromodulation can be used for treatinga patient (e.g., a patient having one or more risk factors associatedwith developing an eating disorder) prior to the development of one ormore comorbid conditions (e.g., substance and alcohol abuse/addiction,depression and/or depressive disorder, psychotic and/or personalitydisorders, cardiovascular disease, stroke, hypertension, obesity (e.g.,high BMI), metabolic disorders, such as type 2 diabetes, cancer, andcognitive impairment (e.g., leading to dementia), etc.) and for reducinga risk associated with developing an eating disorder.

In other embodiments, therapeutically-effective renal neuromodulationcan be used to treat eating disorder patients or patients diagnosed withan eating disorder to reduce an incidence of cardiovascular disease(e.g., coronary heart disease, etc.) or a cardiovascular event (e.g.,MI, stroke, etc.) in the patient. In further embodiments,therapeutically-effective renal neuromodulation can be used for treatinga patient having an eating disorder to improve one or more parametersassociated with cardiovascular health, or to reduce a severity of acardiovascular condition.

While sympathetic drive regulation can have adaptive utility inmaintaining homeostasis or in preparing many organs in the body for arapid response to environmental factors, chronic activation of the SNS(e.g., associated with acute stress syndrome, chronic stress, primaryaging, age-associated obesity, etc.) is a common maladaptive responsethat can contribute to diseases/conditions (e.g., hypertension, systemicor localized inflammation, vascular remodeling, atherosclerosis,obesity, insulin resistance, metabolic syndrome, etc.) or predisposeindividuals to psychophysiological adaptations that can increase apatient's risk of developing an eating disorder and/or drive progressionand/or severity of an eating disorder in a patient. Excessive activationof the renal sympathetic nerves in particular has been identifiedexperimentally and in humans as a likely contributor to the complexpathophysiology of hypertension, states of volume overload (such asheart failure), systemic inflammation, and progressive renal disease. Asexamples, radiotracer dilution has demonstrated increased renalnorepinephrine spillover rates in patients with essential hypertension.

Aspects of the present technology include targeting renal nerve fibersfor neuromodulation in patients (1) having been diagnosed with an eatingdisorder, (2) demonstrating one more physiological and/or psychologicalsymptoms associated with an eating disorder, and/or (3) having anincreased risk associated with developing an eating disorder. Targetingrenal nerve fibers for neuromodulation in patients can effectivelyattenuate neural traffic along the sympathetic nerves. Without beingbound by theory, attenuation of neural traffic along renal sympatheticnerves can be used, for example, to treat or prohibit one or morehallmark symptoms associated with an eating disorder, decrease systemicinflammatory responses associated with an eating disorder, and/ordecrease a level of severity of an eating disorder and/or reduce anumber of symptoms associated with an eating disorder in the patient. Inyet another embodiment, attenuation of neural traffic along renalsympathetic nerves in an individual having one or more risk factorsassociated with developing an eating disorder can be used for reducing arisk associated with developing an eating disorder.

As discussed above, several diseases and conditions have highcomorbidity with an eating disorder diagnosis, including, for example,substance and alcohol abuse/addiction, depression and/or depressivedisorder, anxiety disorder (e.g., general anxiety disorder, socialanxiety disorder), PTSD, psychotic and/or personality disorders,cardiovascular disease, stroke, hypertension, obesity (e.g., high BMI),metabolic disorders, such as type 2 diabetes, cancer, chronic kidneydisease, peripheral artery disease, and cognitive impairment (e.g.,leading to dementia). In certain embodiments, patients having an eatingdisorder and one or more comorbid conditions and/or diseases can betreated with renal neuromodulation to treat and/or reduce severity ofthe eating disorder and/or the one or more comorbid conditions/diseases.In another example, renal neuromodulation can be used to therapeuticallytreat a patient diagnosed with an eating disorder for preventing and/orreducing an incidence of developing one or more comorbidconditions/diseases, including those conditions/diseases wherein chronicSNS activity is known to be a contributing factor (e.g., hypertension,cardiovascular disease, etc.).

In one example, renal neuromodulation can be used to reduce a patient'ssystolic blood pressure, including a MSBP and/or a nocturnal bloodpressure level. In another example, renal neuromodulation can be used toincrease heart rate variability (e.g., the beat-to-beat fluctuations inheart rate) in a patient. In other embodiments, attenuation of neuraltraffic along renal sympathetic nerves can be used to treat or preventmetabolic disorders, obesity and/or insulin resistance in the patienthaving an eating disorder or at increased risk associated withdeveloping an eating disorder. In yet a further embodiment, renalneuromodulation can be used to lower one or more levels of inflammatorybiomarkers in a patient.

Certain effects of chronic SNS activation (such as resulting fromchronic psychological stress) that take place prior to experiencingeating disorder symptoms may be associated with an increased risk ofdeveloping an eating disorder. Many of these effects may not yieldnoticeable signs or symptoms associated with a disease; however, theeffects of chronic SNS activation can cause unseen damage to cardiactissue, brain tissue, and/or vascular tissue, as well as disrupt normalneurophysiological and hormonal balances throughout the body prior tothe appearance of quantifiable disease indicators typically associatedwith maladaptive SNS activation and/or prior to exposure to experiencingeating disorder symptoms in the predisposed or at-risk individual.Accordingly, in one embodiment, neuromodulation treatment can be used totreat patients having a high risk of developing an eating disorder. Forexample, patients may present one or more risk factors for developing aneating disorder (e.g., having been diagnosed with chronic stress, havingan elevated heart rate, having reduced heart rate variability, havingelevated cortisol levels and/or CRH levels, presenting withglucocorticoid resistance, elevated CAR, low levels of central NPY,having elevated systemic plasma levels of inflammatory biomarkers (e.g.,IL-6, IL-8, TNF-α, CRP, etc.), having high blood pressure, having agenetic predisposition (e.g., polymorphisms in genes encoding for NR3C1,FKBP5, CRHR1, TNF-α, etc.). In other examples, such patients having ahigh risk of developing an eating disorder may present one or moresocial or demographic risk factors for the development of an eatingdisorder (e.g., adverse childhood experience(s), personal or familyhistory of having an eating disorder, depression or mental illness,anxiety disorder, experiencing adverse life events, prior exposure totrauma, history of substance or alcohol abuse, being in a stressfulsituation or relationship, physically inactive, female gender, etc.).

In still further embodiments, neuromodulation treatment can be used totreat patients for improving an eating disorder risk score for a patientdiagnosed with an eating disorder. Such a risk score may be determined,for example, using an eating disorder screening tool for determining aseverity of an eating disorder in the patient. For example, certainpatients can have an eating disorder risk score above a threshold eatingdisorder risk score, can have one or more eating disorder risk factors,have a combination of eating disorder risk factors, etc., and renalneuromodulation can be used to therapeutically reduce (a) systemicplasma levels of norepinephrine from, e.g., spillover from innervationof smooth muscle surrounding blood vessels, (b) systemic plasma levelsof inflammatory biomarkers (e.g., IL-6, IL-8, TNF-α, CRP, etc.), and/or(c) high blood pressure. In other embodiments, neuromodulation treatmentcan be used to increase heart rate variability or decrease MSBP inpatients.

In one embodiment, a patient having extreme or chronicpsychological/mental stress in response to an adverse life event orcondition and presenting with one or more acute stress indicators orother indicators, such as pre-hypertension (e.g., systolic BP of 120-139mmHg/diastolic BP of 80-89 mmHg), hypertension (e.g., systolic BP>140mmHg/diastolic BP>90 mmHg), increased serum levels of IL-6 or CRP,higher levels of glucocorticoid (e.g., cortisol), higher CAR, higherMSBP, decreased heart rate variability, or having other factorspresenting an increased risk of developing an eating disorder (e.g.,persons having experienced a traumatic brain injury, having experiencedtraumatic events, adverse childhood, family history of mental illness,eating disorder-associated genetic polymorphisms, etc.) can be treatedwith renal neuromodulation to reduce a level of renal sympathetic driveand/or reduce a level of systemic norepinephrine spillover incirculating plasma (Schlaich, M. P., et al., Frontiers in Physiology,2012, 3(10): 1-7).

In some embodiments, a patient demonstrating chronic stress indicatorsfor greater than 1 year and presenting with eating disorder symptoms canbe diagnosed with an eating disorder by a physician or qualifiedclinician. In other embodiments, a patient demonstrating chronic stressindicators and eating dysfunction-associated symptoms can present with aqualifying result on an eating disorder screening tool (e.g., tool forassessing an eating disorder diagnosis, tool for assessing an eatingdisorder risk status, etc.). In further embodiments, chronicpsychological stress indicators precipitated by an adverse lifecondition or event can refer to patients at risk of developing an eatingdisorder, and patients may be treated with renal neuromodulation toprevent a future on-set of an eating disorder, reduce a risk factorscore associated with the severity of an eating disorder, reduce aseverity of one or more symptoms associated with an eating disorder, orreduce an incidence of developing one more comorbid conditions/diseases.

Several embodiments of the present technology utilize intravasculardevices that reduce sympathetic nerve activity by applying, for example,radiofrequency (RF) energy to target nerve(s) or target site(s) inpatients presenting one or more physiological symptoms associated withan eating disorder, or having a risk of developing an eating disorder,such as having one or more eating disorder risk factors. In certainembodiments, neuromodulation is used to reduce renal sympathetic nerveactivity in patients having a high risk (e.g., a predisposition orincreased likelihood) of developing an eating disorder, one or moresigns or symptoms associated with eating disorder development, or, infurther embodiments, in patients having been diagnosed with an eatingdisorder. In a particular embodiment, neuromodulation is used to reducerenal sympathetic nerve activity in patients having an eating disorderrisk score (e.g., indicating a status or severity of an eating disorder)above a threshold risk score.

Renal neuromodulation is the partial or complete incapacitation or othereffective disruption of the nerves of the kidneys, including nervesterminating in the kidneys or in structures closely associated with thekidneys. In particular, renal neuromodulation can include inhibiting,reducing, and/or blocking neural communication along neural fibers(i.e., efferent and/or afferent nerve fibers) innervating the kidneys.Such incapacitation can be long-term (e.g., permanent or for periods ofmonths, years, or decades) or short-term (e.g., for periods of minutes,hours, days, or weeks). While long-term disruption of the renal nervescan be desirable for preventing incidence of or treating an eatingdisorder, reducing a severity of an eating disorder, or for alleviatingsymptoms and other sequelae associated with an eating disorder overlonger periods of time, short-term modulation of the renal nerves mayalso be desirable. For example, some patients may benefit fromshort-term renal nerve modulation to address acute symptoms presentingduring or following an adverse life event or condition, such ashyperarousal, social or other anxiety, PTSD, mood swings, or otherstress/eating-related behavioral changes. In particular, some patientsmay benefit from short-term renal nerve modulation as adjuvant therapyto increase effectiveness of co-administered drugs (e.g., anti-anxietydrugs, antidepressant drugs, anti-psychotic drugs, anti-inflammatorymedications (e.g., antihistamines), anti-hypertensive drugs, andsleeping medications (e.g., sedatives) among others administered tosupport patients), and/or psychotherapy (e.g., cognitive-behavioraltherapy, interpersonal therapy, etc.).

FIG. 2 is an enlarged anatomic view of nerves innervating a left kidney50 of a patient. As FIG. 2 shows, the kidney 50 is innervated by a renalplexus 52, which is intimately associated with a renal artery 54. Therenal plexus 52 is an autonomic plexus that surrounds the renal artery54 and is embedded within the adventitia of the renal artery 54. Therenal plexus 52 extends along the renal artery 54 until it arrives atthe substance of the kidney 50, innervating the kidneys whileterminating in the blood vessels, the juxtaglomerular apparatus, and therenal tubules (not shown). Fibers contributing to the renal plexus 52arise from the celiac ganglion (not shown), the superior mesentericganglion (not shown), the aorticorenal ganglion 56 and the aortic plexus(not shown). The renal plexus 52, also referred to as the renal nerve,is predominantly comprised of sympathetic components. There is no (or atleast very minimal) parasympathetic innervation of the kidney 50.

Preganglionic neuronal cell bodies are located in the intermediolateralcell column of the spinal cord (renal sympathetic nerves arise fromT10-L2, FIG. 1 ). Referring to FIGS. 1 and 2 together, preganglionicaxons pass through the paravertebral ganglia (they do not synapse) tobecome the lesser splanchnic nerve, the least splanchnic nerve, thefirst lumbar splanchnic nerve, and the second lumbar splanchnic nerve,and they travel to the celiac ganglion (FIG. 1 ), the superiormesenteric ganglion (FIG. 1 ), and the aorticorenal ganglion 56 (FIG. 2). Postganglionic neuronal cell bodies exit the celiac ganglion, thesuperior mesenteric ganglion, and the aorticorenal ganglion 56 to therenal plexus 52 and are distributed to the renal vasculature.

It has previously been shown that stimulation of renal efferent nervesdirectly affects neural regulation components of renal function that areconsiderably stimulated in disease states characterized by heightenedsympathetic tone such as, for example, increased blood pressure inhypertensive patients. As provided herein, renal neuromodulation islikely to be valuable in the treatment of an eating disorder and/orsymptoms associated with an eating disorder. Renal neuromodulation isalso likely to be valuable in the prevention of developing an eatingdisorder in certain at-risk individuals (e.g., individuals havingexperienced adverse life events or circumstances and/or presenting oneor more chronic stress indicators or biomarkers indicating a highlikelihood of developing an eating disorder).

Renal neuromodulation may also likely to be valuable in the treatment ofdiseases and conditions that are associated with eating disorders and/orincreased SNS tone such as, for example, cardiovascular disease,hypertension, increased blood pressure variability, systemicinflammation, endothelial dysfunction, vascular inflammation, vesselremodeling and/or hardening, atherosclerosis, and metabolic disordersamong others. In particular, renal neuromodulation along the renalartery and/or within branches of the renal artery as described in U.S.patent application Ser. No. 14/839,893, filed Aug. 28, 2015 andincorporated herein by reference in its entirety, is expected to reducerenal sympathetic drive in the kidney, thereby reducing the negativeimpact of SNS activation on aspects of these and other conditionsassociated with physiological changes that have impact on psychologicaland cognitive health. As such, renal neuromodulation is also likely tobe particularly valuable in patients having one or more clinicalconditions characterized by increased overall and particularly renalsympathetic activity, such as cardiovascular disease, hypertension,increased blood pressure variability, low heart rate variability,systemic inflammation, chronic vascular inflammation, endothelialdysfunction, metabolic syndrome, insulin resistance, diabetes, anxietydisorder, and depression among others.

As the reduction of afferent neural signals contributes to the systemicreduction of sympathetic tone/drive, renal neuromodulation might also beuseful in preventing an eating disorder. For example, a reduction incentral sympathetic drive may reduce and/or improve measurablephysiological parameters typically associated with the development of aneating disorder, prior to on-set of core eating disorder symptoms.Alternatively, a reduction in central sympathetic drive may, forexample, reduce an elevated heart rate, improved blood pressure, improveheart rate variability, increase blood flow to the brain, reducecerebrovascular inflammation, reduce systemic inflammation, and/orimprove other chronic stress-related symptoms such as depression andsymptoms associated with excessive anxiety (e.g., uncontrollableworrying or fear, panic attacks, etc.).

Other psychologically and/or neurologically related conditions, such as,e.g., depression and disabilities associated with excessive anxiety, aswell as other conditions presented as comorbid with eating disorderssuch as, for example, cardiovascular disease, stroke, hypertension,chronic kidney disease, high BMI (e.g., obesity), metabolic disorder(e.g., diabetes) and substance and/or alcohol abuse, may also betreatable or preventable in eating disorder patients using renalneuromodulation. In some instances, therapeutically-effective renalneuromodulation may improve one or more measurable physiologicalparameters associated with a comorbid disease or condition in thepatient without substantially improving the eating disorder in thepatient.

Intravascular devices that reduce sympathetic nerve activity byapplying, for example, RF energy to a target site in the renal arteryhave recently been shown to reduce blood pressure in patients withtreatment-resistant hypertension. The renal sympathetic nerves arisefrom T10-L2 and follow the renal artery to the kidney. The sympatheticnerves innervating the kidneys terminate in the blood vessels, thejuxtaglomerular apparatus, and the renal tubules. Stimulation of renalefferent nerves results in increased renin release (and subsequentrenin-angiotensin-aldosterone system (RAAS) activation) and sodiumretention and decreased renal blood flow. These neural regulationcomponents of renal function are considerably stimulated in diseasestates characterized by heightened sympathetic tone and likelycontribute to increased blood pressure in patients with an eatingdisorder and increased levels of peripheral inflammatory markers, suchas IL-6 and CRP, in patients with an eating disorder experiencing a hostof inflammatory challenges.

Pharmacologic strategies to thwart the consequences of renal efferentsympathetic stimulation include centrally acting sympatholytic drugs,beta blockers (intended to reduce renin release), angiotensin convertingenzyme inhibitors and receptor blockers (intended to block the action ofangiotensin II and aldosterone activation consequent to renin release),and diuretics (intended to counter the renal sympathetic mediated sodiumand water retention). These pharmacologic strategies, however, havesignificant limitations including limited efficacy, compliance issues,side effects, and others. Recently, intravascular devices that reducesympathetic nerve activity by applying an energy field to a target sitein the renal blood vessel (e.g., via radio frequency (RF) ablation) havebeen shown to be efficacious in reducing blood pressure, decreasingblood pressure variability, decreasing nocturnal blood pressure,reducing MSBP, improving arterial stiffness and reducing mediators ofsystemic inflammation in patients with treatment-resistant hypertension.

Various techniques can be used to partially or completely incapacitateneural pathways, such as those innervating the kidney. The purposefulapplication of energy (e.g., electrical energy, thermal energy) totissue can induce one or more desired thermal heating and/or coolingeffects on localized regions along all or a portion of a renal bloodvessel (e.g., renal artery, renal arterial branch, renal ostium, renalvein) and adjacent regions of the renal plexus RP, which lay intimatelywithin or adjacent to the adventitia of the renal blood vessel. Someembodiments of the present technology, for example, includeelectrode-based or transducer-based approaches, which can be used fortherapeutically-effective neuromodulation. For example, an energydelivery element (e.g., electrode) can be configured to deliverelectrical and/or thermal energy at a treatment site.

By way of theory, targeting both general afferent and efferent renalsympathetic nerves (e.g., via a catheter-based approach, utilizingextracorporeal ultrasound) may cause beneficial effects extending wellbeyond affecting a severity of an eating disorder or a risk associatedwith developing an eating disorder, such as reducing a risk ofdeveloping hypertension, stroke, cardiovascular disease, obesity,metabolic disorder or other end organ damage. As discussed herein, acorrelation between hyperactivity of the SNS and an increased risk ofdeveloping an eating disorder and an increased risk in promoting moresevere eating disorder symptoms has been implicated. There is now alsoevidence that an eating disorder and related symptom severity isassociated with chronic inflammatory responses and sympatheticactivation appears to affect serum levels of peripheral inflammatorymarkers. Additionally, chronic stress, obesity and other cardiovascularmaladies promote hyperactivity (e.g., overactivity) of the sympatheticnervous system throughout the body. For example, when experiencingstress, including chronic stress, hormonal and neural information (e.g.,sensory afferent input) is received by the CNS, which in turn furtherelevates sympathetic tone via efferent signaling throughout the body.Some aspects of methods of treating patients having an eating disorderor having one or more risk factors, including a high risk score, for thedevelopment of an eating disorder, using sympathetic neuromodulation areat least in part derived from the recognition described herein that thekidneys may contribute to elevated central sympathetic drive.

Several aspects of the current technology are configured to reduce renalsympathetic nerve activity within or near the kidney(s) to reducelocalized release of norepinephrine. Several properties of the renalvasculature may inform the design of treatment devices and associatedmethods for achieving target sympathetic neuromodulation, for example,via intravascular access, and impose specific design requirements forsuch devices. Specific design requirements for renal neuromodulation mayinclude accessing the renal artery, a ureter, a renal pelvis, a majorrenal calyx, a minor renal calyx, and/or another suitable structure;facilitating stable contact between the energy delivery elements of suchdevices and a luminal surface or wall of the suitable targetedstructure, and/or effectively modulating the renal nerves with theneuromodulatory apparatus.

Intravascular devices that reduce sympathetic nerve activity byapplying, for example, RF energy to a treatment site in the renal arteryhave recently been shown to reduce renal sympathetic drive, renalnorepinephrine spillover, and whole body norepinephrine spillover. Renalneuromodulation is expected to reduce renal sympathetic neural activity,and since the reduction of afferent neural signals contributes to thesystemic reduction of sympathetic tone/drive, renal neuromodulation is auseful technique in addressing certain risk factors and symptomsassociated with an eating disorder that are attributable to systemicsympathetic hyperactivity. For example, as previously discussed, areduction in central sympathetic drive may treat an eating disorderincluding reducing a severity of one or more symptoms associated with aneating disorder, reduce a likelihood of developing an eating disorder,as well as improve other comorbid disease manifestations (e.g.,hypertension, cardiovascular disease, stroke, metabolic disorders,insulin resistance, diabetes, systemic inflammation, depression, etc.)associated with sympathetic hyperactivity.

Accordingly, renal neuromodulation is expected to be useful in treatingan eating disorder, reducing a severity of one or more symptoms inpatients afflicted with an eating disorder, preventing and/or treatingone or more comorbid conditions or diseases associated with an eatingdisorder or preventing an incidence of developing an eating disorder inpatients presenting certain risk factors. The beneficial effect of renalneuromodulation with respect to a risk associated with development of aneating disorder is expected to apply to patients who do not currentlymeet the diagnostic standard for an eating disorder diagnosis (e.g.,under DSM-5), for example, regardless of the baseline renal sympatheticneural activity or the baseline level of norepinephrine in plasma (e.g.,whole body norepinephrine spillover). For example, renal neuromodulationin accordance with embodiments of the present technology can improve oneor more measurable physiological parameters corresponding to an eatingdisorder risk factor or status (e.g., level of severity of diagnosis) inthe patient when baseline renal sympathetic neural activity is normal,below normal, or above normal (e.g., hyperactive or overactive).Likewise, renal neuromodulation in accordance with additionalembodiments of the present technology can improve one or more measurablephysiological parameters corresponding to an eating disorder risk factoror an eating disorder status (e.g., level of severity of diagnosis) inthe patient when baseline central sympathetic drive, baselinenorepinephrine spillover in plasma, and/or whole body norepinephrinespillover is normal, below normal, or above normal (e.g., hyperactive oroveractive). Such an improvement in one or more measurable physiologicalparameters corresponding to an eating disorder risk factor or an eatingdisorder status (e.g., level of severity of diagnosis) in the patientcan reduce a risk associated with developing an eating disorder in thatpatient or can reduce symptom severity and/or effectively treat anafflicted patient diagnosed with an eating disorder.

III. METHODS FOR TREATING EATING DISORDERS AND/OR REDUCING A RISKASSOCIATED WITH DEVELOPING AN EATING DISORDER AND RELATED CONDITIONS

Disclosed herein are several embodiments of methods directed to treatingan incidence of an eating disorder in a patient using catheter-basedrenal neuromodulation. Further embodiments disclosed herein are directedto preventing an incidence of an eating disorder and/or other conditionsassociated with an increased risk of developing an eating disorder in apatient using catheter-based renal neuromodulation. The methodsdisclosed herein may represent various advantages over a number ofconventional approaches and techniques in that they allow for thepotential targeting of elevated sympathetic drive, which may either be acause of several neurological, immune vascular, or other physiologicalrisk factors associated with an eating disorder or a key mediator of thedisorder manifestation. Also, the disclosed methods provide forlocalized treatment and limited duration treatment regimens (e.g.,one-time treatment), thereby reducing patient long-term treatmentcompliance issues.

In certain embodiments, the methods provided herein comprise performingrenal neuromodulation, thereby decreasing sympathetic renal nerveactivity, for example, for the purposes of being able to provide one ormore of a reduction in a number of eating disorder risk factors, areduction in severity of one or more eating disorder risk factors, areduction in a calculated eating disorder risk score, a reversal invascular damage facilitated by sympathetic activity, or a reduction insystemic inflammation. For example, renal neuromodulation is expected toreduce a level of central sympathetic activity that may contribute toone more underlying causes of eating disorders.

Renal neuromodulation may be repeated one or more times at variousintervals until a desired sympathetic nerve activity level or anothertherapeutic benchmark is reached. In one embodiment, for example, adecrease in sympathetic nerve activity may be observed via a marker ofsympathetic nerve activity in patients, such as decreased levels ofplasma norepinephrine (noradrenaline), changes in levels of systemicrenin in plasma, changes in levels of angiotensin II in plasma, and/orchanges in levels of systemic aldosterone in plasma. Other measures ormarkers of sympathetic nerve activity can include MSNA, norepinephrinespillover, and/or heart rate variability. In some instances, a decreasein SNS activity can be observed as a decrease in norepinephrine andmetabolites thereof (e.g., vanillomandelic acid (VMA)) in urine. Inanother embodiment, other measurable physiological parameters ormarkers, such as improved baroreceptor sensitivity, improved heart rateresponses to stimuli/stress, improved heart rate variability, improvedskin conductance, improved blood pressure control (e.g., lower bloodpressure), improved blood pressure variability (e.g., improved MSBP,improved nocturnal blood pressure “dipping”), lower levels of peripheralinflammatory biomarkers (e.g., IL-6, IL-8, TNF-α, CRP, etc.), improvedlevels of NPY, reduced cortisol levels, reduced CAR, reducedglucocorticoid resistance, improved brain neural activity (e.g., in thehippocampus and other brain regions), changes in aldosterone-to-reninratio (ARR), changes in a salt suppression test, changes in blood plasmalevels of potassium, improved blood glucose regulation, etc., can beused to assess efficacy of the thermal modulation treatment for patientsdiagnosed as having an eating disorder or for patients having one ormore risk factors for developing an eating disorder, and/or having acalculated eating disorder risk score above a threshold eating disorderrisk score. In certain embodiments, renal neuromodulation may berepeated one or more times at various intervals until a desiredsympathetic nerve activity level or another therapeutic benchmark isreached for such patients.

In certain embodiments of the methods provided herein, renalneuromodulation is expected to result in a change in sympathetic nerveactivity and/or in other measurable physiological parameters or markers,over a specific timeframe. For example, in certain of these embodiments,sympathetic nerve activity levels are decreased over an extendedtimeframe, e.g., within 1 month, 2 months, 3 months, 6 months, 9 monthsor 12 months post-neuromodulation.

In several embodiments, the methods disclosed herein may comprise anadditional step of measuring sympathetic nerve activity levels, and incertain of these embodiments, the methods can further comprise comparingthe activity level to a baseline activity level. Such comparisons can beused to monitor therapeutic efficacy and to determine when and if torepeat the neuromodulation procedure. In certain embodiments, a baselinesympathetic nerve activity level is derived from the subject undergoingtreatment. For example, baseline sympathetic nerve activity level may bemeasured in the subject at one or more timepoints prior to treatment. Abaseline sympathetic nerve activity value may represent sympatheticnerve activity at a specific timepoint before neuromodulation, or it mayrepresent an average activity level at two or more timepoints prior toneuromodulation. In certain embodiments, the baseline value is based onsympathetic nerve activity immediately prior to treatment (e.g., afterthe subject has already been catheterized). Alternatively, a baselinevalue may be derived from a standard value for sympathetic nerveactivity observed across the population as a whole or across aparticular subpopulation. In certain embodiments, post-neuromodulationsympathetic nerve activity levels are measured in extended timeframespost-neuromodulation, e.g., 3 months, 6 months, 12 months or 24 monthspost-neuromodulation.

In certain embodiments of the methods provided herein, the methods aredesigned to decrease sympathetic nerve activity to a target level. Inthese embodiments, the methods include a step of measuring sympatheticnerve activity levels post-neuromodulation (e.g., 6 monthspost-treatment, 12 months post-treatment, etc.) and comparing theresultant activity level to a baseline activity level as discussedabove. In certain of these embodiments, the treatment is repeated untilthe target sympathetic nerve activity level is reached. In otherembodiments, the methods are simply designed to decrease sympatheticnerve activity below a baseline level without requiring a particulartarget activity level.

In one embodiment, measured norepinephrine content (e.g., assessed viatissue biopsy, assessed in real-time via intravascular blood collectiontechniques, assessed in real-time via urine, etc.) can be reduced (e.g.,at least about 5%, 10%, 20% or by at least 40%) in the patient within,for example, about three months after at least partially inhibitingsympathetic neural activity in nerves proximate a renal blood vessel.

In one embodiment, renal neuromodulation may be performed on a patienthaving one or more risk factors or symptoms associated with an eatingdisorder to improve the physiological state of at least one of theeating disorder risk factors. In some embodiments, for example, renalneuromodulation may result in a reduction in a patient's heart rateunder stress, may raise heart rate variability, lower a MSBP, lower anocturnal blood pressure level, reduce systolic blood pressure, reduceblood pressure variability, increase baroreceptor sensitivity, lowerskin conductance, reduce a serum level of an inflammatory biomarker, orreduce a level of insulin resistance. In a particular example, a patienthaving an eating disorder and decreased heart rate variability (e.g.,SDNN<50 ms) may have heart rate variability within a normal range (e.g.,SDNN>50 ms) after a neuromodulation procedure. In a further example, areduction in MSBP can be, for example, by at least about 5%, 10% or agreater amount as determined by average ambulatory blood pressureanalysis before and after (e.g., 1, 3, 6, or 12 months after) a renalneuromodulation procedure. Likewise, and in yet a further example, areduction in nocturnal blood pressure level can be, for example, by atleast about 5%, 10%, or a greater amount as determined by averageambulatory blood pressure analysis before and after (e.g., 1, 3, 6, or12 months after) a renal neuromodulation procedure.

In the case of systemic inflammation and/or a patient having elevatedserum levels of inflammatory biomarkers, IL-6, IL-8, TNF-α and/or CRP,renal neuromodulation may improve (e.g., reduce a level of) markers ofinflammation (e.g., IL-6, IL-8, TNF-α, CRP), and in some embodiments,provide a reduction in biomarker level, for example, by about 5%, 10%,25%, 45% or a greater amount as determined by blood analysis before andafter (e.g., 1, 3, 6, or 12 months after) a renal neuromodulationprocedure. In an example where the patient has elevated cortisol levels,elevated CRH levels, and/or glucocorticoid resistance, renalneuromodulation may improve (e.g., reduce a level of) cortisol levels,CRH levels, and/or glucocorticoid resistance by about 5%, about 10%,about 20% or greater amount as determined by quantitative analysis(e.g., dexamethasone binding assay, dexamethasone suppression test,radioimmunoassay, CRH stimulation test, etc.). In other embodiments, andin particular afflicted patients, renal neuromodulation may increasearteriole blood flow, reduce a level of atherosclerosis, or reduce adegree of arterial stiffening in the patient by about 5%, 10% or agreater amount as determined by qualitative or quantitative analysis(e.g., computerized tomography (CT) scan, pulse wave velocity (PWV)analysis, angiography, etc.) before and after (e.g., 1, 3, 6, or 12months after) a renal neuromodulation procedure.

In another embodiment, renal neuromodulation may be performed on apatient having a calculated eating disorder risk score associated withan eating disorder status in the patient that is above a thresholdeating disorder risk score. Renal neuromodulation is expected totherapeutically improve the patient's eating disorder risk score andthereby reduce, diminish, reverse or eliminate the eating disorder inthe patient. In one embodiment, a threshold eating disorder risk scoremay be a theoretical risk score (e.g., based on population studies) thatrepresents a cut-off score for an eating disorder diagnosis. In otherembodiments, the threshold eating disorder risk score may be atheoretical risk score that represents an upper limit of acceptableseverity and/or acceptable risk of developing an eating disorder.

In a particular example, a patient may be assessed for a number offactors that have been previously determined to validate an eatingdisorder diagnosis and/or to carry risk for the development of an eatingdisorder (e.g., number or severity of core eating disorder symptoms,genetic/epigenetic factors, number or duration of adverse life events orcircumstances the patient has experienced, number of prior traumaticevents the patient experienced, prior brain injury, presence of abuse orneglect during childhood, presence of personal or family history ofeating disorders, depression or mental illness, history of anxietydisorder, low heart rate variability, elevated cortisol levels, elevatedCAR, low NPY levels, baroreceptor sensitivity, blood pressure, MSBPlevels, nocturnal blood pressure levels, MSNA levels, body mass index,substance abuse/habits, etc.). Using an eating disorder risk scorecalculator tool (e.g., based on epidemiological data), a patient's riskscore can be assessed. For patients having a calculated eating disorderrisk score above the threshold eating disorder risk score (e.g.,signifying an undesirable level of symptom or disorder severity orprobability of having an eating disorder), a renal neuromodulationprocedure is performed. Renal neuromodulation may improve (e.g., lower,reverse, reduce a rate of increase over time, etc.) the patient's eatingdisorder risk score. For example, following a renal neuromodulationprocedure, a patient's calculated eating disorder risk score may reduce(e.g., improve) by about by about 5%, about 10%, about 15%, about 20%,about 25%, about 30%, about 40%, about 50%, about 75%, or a greateramount as determined by the eating disorder risk score calculator tool.Such improvements in a patient's eating disorder risk score may bedetected, for example 1, 3, 6, 12, or 24 months after a renalneuromodulation procedure. In certain embodiments, a threshold riskscore can be variable depending on a number of factors including gender,age, socioeconomic levels, geographical residence, etc. For example, athreshold risk score for a male patient can be greater than a thresholdrisk score for a female patient.

In addition to (or instead of) affecting one or more measurable riskfactors associated with an eating disorder or the development of aneating disorder, renal neuromodulation may efficaciously treat one ormore measurable physiological parameter(s) or sequela(e) correspondingto the progression or severity of an eating disorder in the patient. Forexample, in some embodiments, renal neuromodulation may result in animprovement (e.g., prevent further decline, maintain, or improve) in apatient's cognitive abilities and/or emotional/social functioningabilities as assessed by one or more accepted diagnostic test methods(e.g., screening tools, questionnaires, etc.) for identifying eatingdisorder risk, severity and diagnosis (e.g., PSQI, ESS, ISDI, MEQ, HADS,PHQ-ADS, a VAS, MSLT and/or a polysomnography, etc.). In a specificembodiment, a patient may improve an eating disorder screening testscore, maintain an eating disorder screening test score, or decrease arate of decline (e.g., rate of eating disorder progression) in a testscore over time following a renal neuromodulation procedure. Suchimprovements in a patient's cognitive abilities and/or emotional/socialfunctioning abilities may be detected, for example 1, 3, 6, or 12 monthsafter a renal neuromodulation procedure. In other embodiments,improvements are detected 2, 3, 4, 5 or 10 years after a renalneuromodulation procedure. In some embodiments, an eating diagnostictest score can be improved by about 5%, about 10%, about 15%, about 20%,about 30%, about 40%, about 50%, or about 75%. In other embodiments,patients may report that daily activities are easier following aneuromodulation procedure.

In an example, renal neuromodulation may efficaciously treat one or moreaspects of eating disorder indications associated with an eatingdisorder in the patient. For example, a patient may have an improvement(e.g., a reduction) in the number, the type and/or the duration ofeating disorder indications (e.g., frequency of food restriction, numberof times patient purged following eating, number of binge-eatingepisodes, etc.) following a renal neuromodulation procedure. Suchimprovements in a patient's eating disorder indications may be detected,for example 1, 3, 6, or 12 months after a renal neuromodulationprocedure. In other embodiments, improvements are detected 2 or 3 yearsafter a renal neuromodulation procedure. In some embodiments, thepatient's eating disorder indications can be improved by about 5%, about10%, about 15%, about 20%, about 30%, about 40%, about 50%, or about 75%within 3 to 12 months or within 3 to 6 months following a renalneuromodulation procedure.

In a further example, renal neuromodulation may efficaciously treatadditional aspects of eating disorder symptoms in the patient. Forexample, a patient may have an improvement (e.g., a reduction) in thenumber of instances, the type, and/or the severity of eating disorderindications, such as binge-eating, purging, thinking about body weightor shape, disrupted sleep patterns or poor sleep quality, irritability,excessive anxiety and worry, depression-related symptoms (e.g., sadness,loss of hope, etc.) following a renal neuromodulation procedure. Suchimprovements in a patient's eating disorder symptoms may be detected,for example, 1, 3, 6, or 12 months after a renal neuromodulationprocedure. In other embodiments, improvements are detected 2 or 3 yearsafter a renal neuromodulation procedure. In some embodiments, the levelof eating disorder symptoms (e.g., level of severity, number of eatingdisorder symptoms, the number of days the patient experiences eatingdisorder symptoms within a logged time period, etc.) can be improved byabout 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about50%, or about 75% within, for example, 3 to 12 months or within 3 to 6months following a renal neuromodulation procedure. In some embodiments,the patient can experience complete regression or full recovery from theeating disorder symptoms.

Renal neuromodulation may prevent or reduce an incidence of developingone or more comorbid conditions or diseases in a patient with an eatingdisorder. For example a patient with an eating disorder treated withrenal neuromodulation may have a decreased likelihood of developingpre-hypertension, hypertension, cardiovascular disease, stroke risk,metabolic disorders, insulin resistance, diabetes, systemicinflammation, chronic kidney disease, peripheral artery disease,dementia, or infertility, etc. In other embodiments, a patient with aneating disorder treated with renal neuromodulation may have a decreasedlikelihood of developing depression, an anxiety disorder or other mentaldisorder. In another embodiment, patients with an eating disorder havingone or more comorbid conditions or diseases may have an improvement in(e.g., reduction, maintain a level, slow a rate of progression of) inthe one or more comorbid conditions or diseases and associated symptomsthereof. In a particular example, a pre-hypertensive patient (e.g.,systolic BP of 120-139 mmHg/diastolic BP of 80-89 mmHg) may have bloodpressure below the pre-hypertensive range after a renal neuromodulationprocedure. Likewise, a hypertensive patient (e.g., systolic BP>140mmHg/diastolic BP>90 mmHg) may have blood pressure below thehypertensive range after a renal neuromodulation procedure.Corresponding results may be obtained with angiotensin II levels, plasmaaldosterone concentration, plasma renin activity, and/oraldosterone-to-renin ratio. For example, a reduction in analdosterone-to-renin ratio can be, for example, by at least about 5%,10% or a greater amount (e.g., about 50%, about 80%, about 90%) asdetermined by blood analysis and calculation before and after (e.g., 1,3, 6, or 12 months after) a renal neuromodulation procedure.

Other measurable physiological parameters may also improve followingrenal neuromodulation. For example, a patient may have an improvement in(e.g., reduction, maintain a level of, slow a rate of progression of)atherosclerosis of extracranial and/or intracranial arteries, clinicalmeasurements of aortic and large-artery, small-vessel disease or otheralterations in small arteries providing physiological blood flow, neuralactivity (e.g., in the amygdala, ventromedial prefrontal cortex, dorsalanterior cingulate cortex, hippocampus and/or insular cortex or otherregions involved in the limbic system), following a renalneuromodulation procedure as determined by qualitative or quantitativeanalysis (e.g., CT scan, PWV analysis, angiography, MM, PET scan, etc.)before and after (e.g., 1, 3, 6, or 12 months after; 2, 3, 4, 5 or 10years after) a renal neuromodulation procedure.

As discussed previously, the development of an eating disorder incertain individuals may be related to sympathetic overactivity eitherbefore (e.g., chronic or episodic), during (e.g., at the time of), orfollowing an adverse life event or circumstance, and, correspondingly,the degree of sympathoexcitation in a patient may be related to one ormore of the severity of the clinical presentation of an eating disorder,the number of traumatic events experienced by the patient, whether thepatient has had adversity during childhood, number and duration ofadverse life events or circumstances (e.g., triggering psychologicalstress responses), personal or family history of eating disorders,depression or mental illness, history of cardiovascular disease orstroke, among other psychological, physiological and genetic/epigeneticfactors. The kidneys are positioned to be both a cause (via afferentnerve fibers) and a target (via efferent sympathetic nerves) of elevatedcentral sympathetic drive. In some embodiments, renal neuromodulationcan be used to reduce central sympathetic drive in a patientdemonstrating one or more risk factors for an eating disorder in amanner that treats the patient for an eating disorder and/or to preventan incidence of an eating disorder in the patient in later life. In someembodiments, for example, MSNA can be reduced by at least about 10% inthe patient within about three months after at least partiallyinhibiting sympathetic neural activity in nerves proximate a renalartery of the kidney. Similarly, in some instances whole bodynorepinephrine spillover to plasma can be reduced at least about 20%,about 30%, about 40%, about 45%, about 50% or a greater amount in thepatient within about three months to about 12 months after at leastpartially inhibiting sympathetic neural activity in nerves proximate arenal artery of the kidney. Additionally, measured norepinephrinecontent (e.g., assessed via renal biopsy, assessed in real-time viaintravascular blood collection techniques, assessed in real-time viaurine, etc.) can be reduced (e.g., at least about 5%, 10%, or by atleast 20%) in the patient within about three months after at leastpartially inhibiting sympathetic neural activity in nerves proximate arenal artery innervating the kidney.

In one example, a patient having one or more suspected risk factors foran eating disorder and/or the development of an eating disorder can besubjected to a baseline assessment indicating a first set of measurableparameters corresponding to the one or more risk factors. Suchparameters can include, for example, levels of central sympathetic drive(e.g., MSNA, whole body norepinephrine spillover), measurednorepinephrine content (e.g., assessed via tissue biopsy, plasma orurine), blood pressure, 24-hour blood pressure variability, heart ratevariability, baroreceptor sensitivity, heart rate during stress/stimuli,skin conductance, glucocorticoid levels (e.g., in hair, urine, plasma,etc.), glucocorticoid resistance, CAR level, NPY level, CRH level,inflammatory biomarker levels (e.g., IL-6, IL-8, TNF-α, CRP, etc.),cholesterol levels, blood glucose levels, fasting blood insulin levels,measures of insulin sensitivity, body mass index, perceived cognitivefunctioning level (e.g., self-reporting, third-party reporting, etc.),one or more brain function test scores, and brain/body imaging forvascular remodeling (e.g., arteriole stiffness, arterial blood flow)and/or brain structural alterations (e.g., atrophy, neural activity,etc.). Following baseline assessment, the patient can be subjected to arenal neuromodulation procedure. Such a procedure can, for example,include any of the treatment modalities described herein or anothertreatment modality in accordance with the present technology. Thetreatment can be performed on nerves proximate one or both kidneys ofthe patient. Following the treatment (e.g., 1, 3, 6, or 12 monthsfollowing the treatment; 2, 3, 4, 5 or 10 years following thetreatment), the patient can be subjected to a follow-up assessment. Thefollow-up assessment can indicate a measurable improvement in one ormore physiological parameters corresponding to the one or more suspectedrisk factors for the eating disorder or the development of an eatingdisorder.

The methods described herein address the sympathetic excess that isthought to be an underlying factor in eating disorder progression or acentral mechanism through which multiple eating disorder risk factorsare manifest in patients. Currently, there are no therapies prescribedto address the effects of sympathetic excess in patients suspected ofhaving an eating disorder or a risk of developing an eating disorder.Certain proposed therapies, such as lifestyle alterations (e.g.,exercise, diet, alcohol and other substance/drug avoidance, etc.),cognitive behavioral therapy, blood pressure maintenance (e.g.,administration of anti-hypertensive therapies), anti-anxiety and/oranti-depression medications, sleep aides and medications, and reductionand/or maintenance of cholesterol have significant limitations includinglimited efficacy, undesirable side effects and may be subject to adverseor undesirable drug interactions when used in combination. Moreover, useof any drug regimens (e.g., sleep medications, anti-anxiety,antidepressant, anti-hypertensive, cholesterol-lowering,anti-inflammatory, etc.) can have many challenges, including drugcontraindications and drug adherence (particularly prior to onset ofsymptoms). For example, many of these drug regimens may require thepatient to remain compliant with the treatment regimen starting in earlylife (e.g., prior to on-set of a debilitating mental disorder diagnosis)and continue compliance over time. In contrast, neuromodulation can be aone-time or otherwise limited treatment that would be expected to havedurable benefits to treat eating disorders, reduce severity of an eatingdisorder and/or inhibit the long-term potential of developing an eatingdisorder and thereby achieve a favorable patient outcome.

In some embodiments, patients demonstrating one or more risk factorsassociated with an eating disorder or the development of an eatingdisorder and/or have one or more physiological indicators of sympatheticexcess (e.g., combined with additional risk factors) can be treated withrenal neuromodulation alone. However, in other embodiments, combinationsof therapies can be tailored based on specific conditions and eatingdisorder risk factors in a particular patient. For example, certainpatients can be treated with combinations of therapies such as one ormore conventional therapies for treating an anxiety disorder ordepression, for treating an eating disorders, and/or reducing bloodpressure (e.g., anti-hypertensive drug(s)) and treated with one or moreneuromodulation treatments. In another example, renal neuromodulationcan be combined with cholesterol lowering agents (e.g., statins),anti-inflammatory therapy (e.g., drug(s)), as well as weight loss andlifestyle change recommendations/programs. In certain embodiments, apatient being treated with one or more pharmaceutical drugs for anxietyand/or conditions associated with an eating disorder can be treated withrenal neuromodulation to reduce at least one of a number of or ameasured dosage of the pharmaceutical drugs administered to the patient.

Treatment of eating disorder risk factors or symptoms and conditionsassociated with an eating disorder may refer to preventing thecondition, slowing the onset or rate of development of the condition,reducing the risk of developing the condition, preventing or delayingthe development of symptoms associated with the condition, reducing orending symptoms associated with the condition, generating a complete orpartial regression of the condition, or some combination thereof.

IV. SELECTED EXAMPLES OF NEUROMODULATION MODALITIES

As noted previously, complete or partial neuromodulation of a targetrenal sympathetic nerve in accordance with embodiments of the presenttechnology can be electrically-induced, thermally-induced,chemically-induced, or induced in another suitable manner or combinationof manners at one or more suitable locations along one or more renalblood vessels during a treatment procedure. For example, neuromodulationmay be achieved using various modalities, including for examplemonopolar or bipolar RF energy, pulsed RF energy, microwave energy,laser light or optical energy, magnetic energy, ultrasound energy (e.g.,intravascularly delivered ultrasound, extracorporeal ultrasound,high-intensity focused ultrasound (HIFU)), direct heat energy, radiation(e.g., infrared, visible, gamma), or cryotherapeutic energy, chemicals(e.g., drugs or other agents), or combinations thereof. Where a systemuses a monopolar configuration, a return electrode or ground patch fixedexternally on the subject can be used. In certain embodiments,neuromodulation may utilize one or more devices including, for example,catheter devices such as the Symplicity Spyral™ catheter (Medtronicplc). Other suitable thermal devices are described in U.S. Pat. Nos.7,653,438, 8,347,891, and U.S. patent application Ser. No. 13/279,205,filed Oct. 21, 2011. Other suitable devices and technologies aredescribed in U.S. patent application Ser. No. 13/279,330, filed Oct. 23,2011, International Patent Application No. PCT/US2015/021835, filed Mar.20, 2015, and International Patent Application No. PCT/US2015/013029,filed Jan. 27, 2015. Further, electrodes (or other energy deliveryelements) can be used alone or with other electrodes in amulti-electrode array. Examples of suitable multi-electrode devices aredescribed in U.S. patent application Ser. No. 13/281,360, filed Oct. 25,2011, and U.S. Pat. No. 8,888,773. Other examples of suitable directheat devices are described in International Patent Application No.PCT/US2014/023738 filed Mar. 11, 2014, and U.S. patent application Ser.No. 14/203,933, filed Mar. 11, 2014. All of the foregoing patentreferences are incorporated herein by reference in their entireties.

In those embodiments of the methods disclosed herein that utilizepartial ablation, the level of energy delivered to the target artery andsurrounding tissue may be different than the level that is normallydelivered for complete neuromodulation. For example, partialneuromodulation using RF energy may use alternate algorithms ordifferent power levels than RF energy for complete neuromodulation.Alternatively, partial neuromodulation methods may utilize the samelevel of energy, but delivered to a different depth within the tissue orto a more limited area. In certain embodiments, partial neuromodulationmay be achieved using a device that differs from a device used forcomplete neuromodulation. In certain embodiments, a particular treatmentor energy modality may be more suitable for partial neuromodulation thanother treatment or energy modalities. In some embodiments,neuromodulation may be achieved using one or more chemical agents, suchas by drug delivery. In those embodiments that utilize partialneuromodulation, the methods may utilize the same devices and/or drugdelivery systems used for complete neuromodulation, or they may usecompletely different devices for energy and/or drug delivery.

Thermal effects can include both thermal ablation and non-ablativethermal alteration or damage (e.g., via sustained heating and/orresistive heating) to partially or completely disrupt the ability of anerve to transmit a signal. Such thermal effects can include the heatingeffects associated with electrode-based or transducer-based treatment.For example, a treatment procedure can include raising the temperatureof target neural fibers to a target temperature above a first thresholdto achieve non-ablative alteration, or above a second, higher thresholdto achieve ablation. In some embodiments, the target temperature can behigher than about body temperature (e.g., about 37° C.) but less thanabout 45° C. for non-ablative alteration, and the target temperature canbe higher than about 45° C. for ablation. More specifically, heatingtissue to a temperature between about body temperature and about 45° C.can induce non-ablative alteration, for example, via moderate heating oftarget neural fibers or vascular/luminal structures that perfuse thetarget neural fibers. In cases where vascular structures are affected,the target neural fibers can be denied perfusion resulting in necrosisof the neural tissue. For example, this may induce non-ablative thermalalteration in the fibers or structures. Heating tissue to a targettemperature higher than about 45° C. (e.g., higher than about 60° C.)can induce ablation, for example, via substantial heating of targetneural fibers or of vascular or luminal structures that perfuse thetarget fibers. In some patients, it can be desirable to heat tissue totemperatures that are sufficient to ablate the target neural fibers orthe vascular or luminal structures, but that are less than about 90° C.,e.g., less than about 85° C., less than about 80° C., or less than about75° C. Other embodiments can include heating tissue to a variety ofother suitable temperatures.

In some embodiments, complete or partial neuromodulation of a renalsympathetic nerve can include an electrode-based or transducer-basedtreatment modality alone or in combination with another treatmentmodality. Electrode-based or transducer-based treatment can includedelivering electricity and/or another form of energy to tissue at atreatment location to stimulate and/or heat the tissue in a manner thatmodulates neural function. For example, sufficiently stimulating and/orheating at least a portion of a sympathetic nerve can slow orpotentially block conduction of neural signals to produce a prolonged orpermanent reduction in sympathetic activity. A variety of suitable typesof energy, such as those mentioned above, can be used to stimulateand/or heat tissue at a treatment location. In some embodiments,neuromodulation can be conducted in conjunction with one or more othertissue modulation procedures. An element, transducer, or electrode usedto deliver this energy can be used alone or with other elements,transducers, or electrodes in a multi-element array. Furthermore, theenergy can be applied from within the body (e.g., within the vasculatureor other body lumens in a catheter-based approach or outside thevasculature using, for example, a Natural Orifice TransluminalEndoscopic Surgery or NOTES procedure) and/or from outside the body,e.g., via an applicator positioned outside the body. In someembodiments, energy can be used to reduce damage to non-targeted tissuewhen targeted tissue adjacent to the non-targeted tissue is subjected toneuromodulating cooling.

As an alternative to or in conjunction with electrode-based ortransducer-based approaches, other suitable energy delivery techniques,such as a cryotherapeutic treatment modality, can be used for achievingtherapeutically-effective neuromodulation of a target sympathetic nerve.For example, cryotherapeutic treatment can include cooling tissue at atreatment location in a manner that modulates neural function. Forexample, sufficiently cooling at least a portion of a target sympatheticnerve can slow or potentially block conduction of neural signals toproduce a prolonged or permanent reduction in sympathetic activityassociated with the target sympathetic nerve. This effect can occur as aresult of cryotherapeutic tissue damage, which can include, for example,direct cell injury (e.g., necrosis), vascular or luminal injury (e.g.,starving cells from nutrients by damaging supplying blood vessels),and/or sublethal hypothermia with subsequent apoptosis. Exposure tocryotherapeutic cooling can cause acute cell death (e.g., immediatelyafter exposure) and/or delayed cell death, e.g., during tissue thawingand subsequent hyperperfusion.

Neuromodulation using a cryotherapeutic treatment in accordance withembodiments of the present technology can include cooling a structureproximate an inner surface of a vessel or chamber wall such that tissueis effectively cooled to a depth where sympathetic nerves reside. Forexample, a cooling assembly of a cryotherapeutic device can be cooled tothe extent that it causes therapeutically-effective, cryogenicneuromodulation. In some embodiments, a cryotherapeutic treatmentmodality can include cooling that is not configured to causeneuromodulation. For example, the cooling can be at or above cryogenictemperatures and can be used to control neuromodulation via anothertreatment modality, e.g., to protect tissue from neuromodulating energy.Other suitable cryotherapeutic devices are described, for example, inU.S. patent application Ser. No. 13/279,330, filed Oct. 23, 2011, andincorporated herein by reference in its entirety.

Cryotherapeutic treatment can be beneficial in certain embodiments. Forexample, rapidly cooling tissue can provide an analgesic effect suchthat cryotherapeutic treatment can be less painful than other treatmentmodalities. Neuromodulation using cryotherapeutic treatment cantherefore require less analgesic medication to maintain patient comfortduring a treatment procedure compared to neuromodulation using othertreatment modalities. Additionally, reducing pain can reduce patientmovement and thereby increase operator success and/or reduce proceduralcomplications. Cryogenic cooling also typically does not causesignificant collagen tightening, and therefore is not typicallyassociated with vessel stenosis. In some embodiments, cryotherapeutictreatment can include cooling at temperatures that can cause therapeuticelements to adhere to moist tissue. This can be beneficial because itcan promote stable, consistent, and continued contact during treatment.The typical conditions of treatment can make this an attractive featurebecause, for example, patients can move during treatment, cathetersassociated with therapeutic elements can move, and/or respiration cancause organs and tissues to rise and fall and thereby move the arteriesand other structures associated with these organs and tissues. Inaddition, blood flow is pulsatile and can cause structures associatedwith the kidneys to pulse. Cryogenic adhesion also can facilitateintravascular or intraluminal positioning, particularly inrelatively-small structures (e.g., renal branch arteries) in whichstable intravascular or intraluminal positioning can be difficult toachieve.

The use of ultrasound energy can be beneficial in certain embodiments.Focused ultrasound is an example of a transducer-based treatmentmodality that can be delivered from outside the body (i.e.,extracorporeal). In some embodiments, focused ultrasound treatment canbe performed in close association with imaging, e.g., magneticresonance, computed tomography, fluoroscopy, ultrasound (e.g.,intravascular or intraluminal), optical coherence tomography, or anothersuitable imaging modality. For example, imaging can be used to identifyan anatomical position of a treatment location, e.g., as a set ofcoordinates relative to a reference point. The coordinates can then beentered into a focused ultrasound device configured to change thedistance from source to target, power, angle, phase, or other suitableparameters to generate an ultrasound focal zone at the locationcorresponding to the coordinates. In some embodiments, the focal zonecan be small enough to localize therapeutically-effective heating at thetreatment location while partially or fully avoiding potentially harmfuldisruption of nearby structures. To generate the focal zone, theultrasound device can be configured to pass ultrasound energy through alens, and/or the ultrasound energy can be generated by a curvedtransducer or by multiple transducers in a phased array (curved orstraight). In certain embodiments, the ultrasound device may be acatheter device with an ultrasound transducer or an array of ultrasoundtransducers on its distal tip. In other embodiments the ultrasounddevice may comprise a cylindrical transducer. In certain embodimentswherein the ultrasound device is being used to perform partial ablation,the device may include discrete and/or forward-facing transducers thatcan be rotated and inserted at specific conditions, thereby allowing formore discrete lesion formation. In other embodiments, however, theextracorporeal and/or intravascular ultrasound devices may havedifferent arrangements and/or different features.

In some embodiments, neuromodulation can be effected using achemical-based treatment modality alone or in combination with anothertreatment modality. Neuromodulation using chemical-based treatment caninclude delivering one or more chemicals (e.g., drugs or other agents)to tissue at a treatment location in a manner that modulates neuralfunction. The chemical, for example, can be selected to affect thetreatment location generally or to selectively affect some structures atthe treatment location over other structures. In some embodiments, thechemical can be guanethidine, vincristine, ethanol, phenol, aneurotoxin, or another suitable agent selected to alter, damage, ordisrupt nerves. In some embodiments, energy (e.g., light, ultrasound, oranother suitable type of energy) can be used to activate the chemicaland/or to cause the chemical to become more bioavailable. A variety ofsuitable techniques can be used to deliver chemicals to tissue at atreatment location. For example, chemicals can be delivered via one ormore needles originating outside the body or within the vasculature orother body lumens (see, e.g., U.S. Pat. No. 6,978,174, the disclosure ofwhich is hereby incorporated by reference in its entirety). In anintravascular example, a catheter can be used to intravascularlyposition a therapeutic element including a plurality of needles (e.g.,micro-needles) that can be retracted or otherwise blocked prior todeployment. In other embodiments, a chemical can be introduced intotissue at a treatment location via simple diffusion through a vesselwall, electrophoresis, or another suitable mechanism. Similar techniquescan be used to introduce chemicals that are not configured to causeneuromodulation, but rather to facilitate neuromodulation via anothertreatment modality. Examples of such chemicals include, but are notlimited to, anesthetic agents and contrast agents.

Renal neuromodulation in conjunction with the methods and devicesdisclosed herein may be carried out at a location proximate (e.g., at ornear) a vessel or chamber wall (e.g., a wall of a renal artery, one ormore branch vessels from the renal artery, a ureter, a renal pelvis, amajor renal calyx, a minor renal calyx, and/or another suitablestructure), and the treated tissue can include tissue proximate thetreatment location. For example, with regard to a renal artery, atreatment procedure can include modulating nerves in the renal plexus,which lay intimately within or adjacent to the adventitia of the renalartery.

In certain embodiments, monitoring, assessing and/or determiningneuromodulation efficacy can be accomplished by detecting changes in thelevel of one or more surrogate biomarkers (e.g., a biomarker thatdirectly or indirectly correlates with sympathetic nerve activity in thepatient, a biomarker that directly or indirectly correlates withhypertension, arterial stiffness and/or an inflammatory response in thepatient) in serum, plasma and/or urine in response to neuromodulation.Systems and method for monitoring the efficacy of neuromodulation bymeasuring the levels of one or more biomarkers associated withneuromodulation including, for example, proteins or non-proteinmolecules that exhibit an increase or decrease in level or activity inresponse to neuromodulation are described in, e.g., International PatentApplication No. PCT/US2013/030041, filed Mar. 8, 2013, and InternationalPatent Application No. PCT/US2015/047568, filed Aug. 28, 2015, thedisclosures of which are incorporated herein by reference in theirentireties. In other embodiments, measured levels of protein ornon-protein molecules (e.g., associated with norepinephrine spillover,associated with inflammatory responses, etc.) that exhibit an increaseor decrease in level or activity in response to targeted neuromodulationcan be assessed pre- and post-neuromodulation in tissue biopsies.

V. SELECTED EMBODIMENTS OF RENAL NEUROMODULATION SYSTEMS AND DEVICES

FIG. 3 illustrates a renal neuromodulation system 10 configured inaccordance with an embodiment of the present technology. The system 10,for example, may be used to perform therapeutically-effective renalneuromodulation on a patient (a) to reduce the risk of occurrence of aneating disorder, (b) to reduce a calculated eating disorder risk scorecorresponding to an eating disorder status, (c) to reduce a severity ofneurological symptoms relating to an eating disorder, and/or (d) totreat and/or prevent development of one or more comorbidconditions/diseases associated with an eating disorder (e.g.,hypertension, cardiovascular disease, stroke risk, metabolic disorders,insulin resistance, diabetes, systemic inflammation, dementia, chronickidney disease, etc.). In one embodiment, the patient may be diagnosedwith increased overall sympathetic activity, and, in particular,conditions associated with central sympathetic overstimulation andincreased risk of developing an eating disorder, such as hypertension,blood pressure variability, systemic inflammation, anxiety, chronicstress, depression, cardiovascular disease, history of stroke or TIA,obesity, metabolic syndrome, insulin resistance and diabetes, amongothers.

The system 10 includes an intravascular treatment device 12 operablycoupled to an energy source or console 26 (e.g., a RF energy generator,a cryotherapy console). In the embodiment shown in FIG. 3 , thetreatment device 12 (e.g., a catheter) includes an elongated shaft 16having a proximal portion 18, a handle 34 at a proximal region of theproximal portion 18, and a distal portion 20 extending distally relativeto the proximal portion 18. The treatment device 12 further includes aneuromodulation assembly or treatment section 21 at the distal portion20 of the shaft 16. The neuromodulation assembly 21 can be configured toablate nerve tissue and/or for monitoring one or more physiologicalparameters within the vasculature. Accordingly, a neuromodulationassembly 21 suitable for ablation may include one or more electrodes,transducers, energy-delivery elements or cryotherapeutic coolingassemblies. Neuromodulation assemblies 21 suitable for monitoring mayalso include a nerve monitoring device and/or blood collection/analysisdevice. In some embodiments, the neuromodulation assembly 21 can beconfigured to be delivered to a renal blood vessel (e.g., a renalartery) in a low-profile configuration.

In one embodiment, for example, the neuromodulation assembly 21 caninclude a single electrode. In other embodiments, the neuromodulationassembly 21 may comprise a basket and a plurality of electrodes carriedby the basket. The electrodes on the basket may be spaced apart fromeach other such that each electrode is approximately 90° apart from aneighboring electrode. In yet another embodiment, the neuromodulationassembly 21 can include a balloon and a plurality of bipolar electrodescarried by the balloon. In still another embodiment, the neuromodulationassembly 21 has a plurality of electrodes arranged along an elongatedmember transformable between a low-profile, delivery configuration(e.g., contained in a delivery catheter) and an expanded, deployedconfiguration in which the elongated member has a helical/spiral shape.In further embodiments, the neuromodulation assembly 21 can include oneor more electrodes configured to deliver ablation energy and/orstimulation energy. In some arrangements, the neuromodulation assembly21 can include one or more sensor(s) for detecting impedance or nervemonitoring signals. In any of the foregoing embodiments, theneuromodulation assembly 21 may comprise an irrigated electrode.

Upon delivery to a target treatment site within a renal blood vessel,the neuromodulation assembly 21 can be further configured to be deployedinto a treatment state or arrangement for delivering energy at thetreatment site and providing therapeutically-effectiveelectrically-induced and/or thermally-induced renal neuromodulation. Insome embodiments, the neuromodulation assembly 21 may be placed ortransformed into the deployed state or arrangement via remote actuation,e.g., via an actuator 36, such as a knob, pin, or lever carried by thehandle 34. In other embodiments, however, the neuromodulation assembly21 may be transformed between the delivery and deployed states usingother suitable mechanisms or techniques.

The proximal end of the neuromodulation assembly 21 can be carried by oraffixed to the distal portion 20 of the elongated shaft 16. A distal endof the neuromodulation assembly 21 may terminate with, for example, anatraumatic rounded tip or cap. Alternatively, the distal end of theneuromodulation assembly 21 may be configured to engage another elementof the system 10 or treatment device 12. For example, the distal end ofthe neuromodulation assembly 21 may define a passageway for engaging aguide wire (not shown) for delivery of the treatment device usingover-the-wire (“OTW”) or rapid exchange (“RX”) techniques. The treatmentdevice 12 can also be a steerable or non-steerable catheter device(e.g., a guide catheter) configured for use without a guide wire. Bodylumens (e.g., ducts or internal chambers) can be treated, for example,by non-percutaneously passing the shaft 16 and neuromodulation assembly21 through externally accessible passages of the body or other suitablemethods.

The console 26 can be configured to generate a selected form andmagnitude of energy for delivery to the target treatment site via theneuromodulation assembly 21. A control mechanism, such as a foot pedal32, may be connected (e.g., pneumatically connected or electricallyconnected) to the console 26 to allow an operator to initiate, terminateand, optionally, adjust various operational characteristics of theconsole 26, including, but not limited to, power delivery. The system 10may also include a remote control device (not shown) that can bepositioned in a sterile field and operably coupled to theneuromodulation assembly 21. The remote control device can be configuredto allow for selective activation of the neuromodulation assembly 21. Inother embodiments, the remote control device may be built into thehandle assembly 34. The console 26 can be configured to deliver thetreatment energy via an automated control algorithm 30 and/or under thecontrol of the clinician. In addition, the console 26 may include one ormore evaluation and/or feedback algorithms 31 to provide feedback to theclinician before, during, and/or after therapy.

The console 26 can further include a device or monitor that may includeprocessing circuitry, such as a microprocessor, and a display 33. Theprocessing circuitry may be configured to execute stored instructionsrelating to the control algorithm 30. The console 26 may be configuredto communicate with the treatment device 12 (e.g., via a cable 28) tocontrol the neuromodulation assembly and/or to send signals to orreceive signals from the nerve monitoring device. The display 33 may beconfigured to provide indications of power levels or sensor data, suchas audio, visual or other indications, or may be configured tocommunicate information to another device. For example, the console 26may also be configured to be operably coupled to a catheter lab screenor system for displaying treatment information, such as nerve activitybefore and/or after treatment.

In certain embodiments, a neuromodulation device for use in the methodsdisclosed herein may combine two or more energy modalities. For example,the device may include both a hyperthermic source of ablative energy anda hypothermic source, making it capable of, for example, performing bothRF neuromodulation and cryo-neuromodulation. The distal end of thetreatment device may be straight (for example, a focal catheter),expandable (for example, an expanding mesh or balloon), or have anyother configuration. For example, the distal end of the treatment devicecan be at least partially helical/spiral in the deployed state.Additionally or alternatively, the treatment device may be configured tocarry out one or more non-ablative neuromodulatory techniques. Forexample, the device may comprise a means for diffusing a drug orpharmaceutical compound at the target treatment area (e.g., a distalspray nozzle).

VI. SELECTED EXAMPLES OF TREATMENT PROCEDURES FOR RENAL NEUROMODULATION

A. Achieving Intravascular Access to the Renal Artery

In accordance with the present technology, neuromodulation of a leftand/or right renal plexus RP, which is intimately associated with a leftand/or right renal artery, may be achieved through intravascular access.As FIG. 4A shows, blood moved by contractions of the heart is conveyedfrom the left ventricle of the heart by the aorta. The aorta descendsthrough the thorax and branches into the left and right renal arteries.Below the renal arteries, the aorta bifurcates at the left and rightiliac arteries. The left and right iliac arteries descend, respectively,through the left and right legs and join the left and right femoralarteries.

As FIG. 4B shows, the blood collects in veins and returns to the heart,through the femoral veins into the iliac veins and into the inferiorvena cava. The inferior vena cava branches into the left and right renalveins. Above the renal veins, the inferior vena cava ascends to conveyblood into the right atrium of the heart. From the right atrium, theblood is pumped through the right ventricle into the lungs, where it isoxygenated. From the lungs, the oxygenated blood is conveyed into theleft atrium. From the left atrium, the oxygenated blood is conveyed bythe left ventricle back to the aorta.

As will be described in greater detail later, the femoral artery may beaccessed and cannulated at the base of the femoral triangle justinferior to the midpoint of the inguinal ligament. A catheter may beinserted percutaneously into the femoral artery through this accesssite, passed through the iliac artery and aorta, and placed into eitherthe left or right renal artery. This route comprises an intravascularpath that offers minimally invasive access to a respective renal arteryand/or other renal blood vessels.

The wrist, upper arm, and shoulder region provide other locations forintroduction of catheters into the arterial system. For example,catheterization of either the radial, brachial, or axillary artery maybe utilized in select cases. Catheters introduced via these accesspoints may be passed through the subclavian artery on the left side (orvia the subclavian and brachiocephalic arteries on the right side),through the aortic arch, down the descending aorta and into the renalarteries using standard angiographic technique.

B. Properties and Characteristics of the Renal Vasculature

Properties and characteristics of the renal vasculature imposechallenges to both access and treatment methods, and to system/devicedesigns. Since neuromodulation of a left and/or right renal plexus RPmay be achieved in accordance with embodiments of the present technologythrough intravascular access, various aspects of the design ofapparatus, systems, and methods for achieving such renal neuromodulationare disclosed herein. Aspects of the technology disclosed herein addressadditional challenges associated with variation of physiologicalconditions and architecture across the patient population and/or withina specific patient across time, as well as in response to diseasestates, such as hypertension, atherosclerosis, vascular disease, chronicinflammatory condition, insulin resistance, diabetes, metabolicsyndrome, etc. For example, the design of the intravascular device andtreatment protocols can address not only material/mechanical, spatial,fluid dynamic/hemodynamic and/or thermodynamic properties, but alsoprovide particular algorithms and feedback protocols for deliveringenergy and obtaining real-time confirmatory results of successfullydelivering energy to an intended target location in a patient-specificmanner.

As discussed previously, a catheter may be advanced percutaneously intoeither the left or right renal artery via a minimally invasiveintravascular path. However, minimally invasive renal arterial accessmay be challenging, for example, because as compared to some otherarteries that are routinely accessed using catheters, the renal arteriesare often extremely tortuous, may be of relatively small diameter,and/or may be of relatively short length. Furthermore, renal arterialatherosclerosis is common in many patients, particularly those withcardiovascular disease. Renal arterial anatomy also may varysignificantly from patient to patient, which further complicatesminimally invasive access. Significant inter-patient variation may beseen, for example, in relative tortuosity, diameter, length, and/oratherosclerotic plaque burden, as well as in the take-off angle at whicha renal artery branches from the aorta. Apparatus, systems and methodsfor achieving renal neuromodulation via intravascular access can accountfor these and other aspects of renal arterial anatomy and its variationacross the patient population when minimally invasively accessing arenal artery. For example, spiral or helical CT technology can be usedto produce 3D images of the vascular features for individual patients,and intravascular path choice as well as device size/diameter, length,flexibility, etc. can be selected based upon the patient's specificvascular features.

In addition to complicating renal arterial access, specifics of therenal anatomy also complicate establishment of stable contact betweenneuromodulatory apparatus and a luminal surface or wall of a renal bloodvessel. When the neuromodulatory apparatus includes an energy deliveryelement, such as an electrode, transducer, or a cryotherapeutic device,consistent positioning and appropriate contact force applied by theenergy or cryotherapy delivery element to the vessel wall, and adhesionbetween the applicator and the vessel wall can be important forpredictability. However, navigation can be impeded by the tight spacewithin a renal artery RA, as well as tortuosity of the artery.Furthermore, establishing consistent contact can be complicated bypatient movement, respiration, and/or the cardiac cycle because thesefactors may cause significant movement of the renal artery RA relativeto the aorta, and the cardiac cycle may transiently distend the renalartery RA (i.e., cause the wall of the artery to pulse). To addressthese challenges, the treatment device or applicator may be designedwith relative sizing and flexibility considerations. For example, therenal artery may have an internal diameter in a range of about 2-10 mmand the treatment device can be delivered using a 3, 4, 5, 6, 7 French,or in some cases, an 8 French sized catheter. To address challengesassociated with patient and/or arterial movement during treatment, thetreatment device and neuromodulation system can be configured to usesensory feedback, such as impedance and temperature, to detectinstability and to alert the operator to reposition the device and/or totemporarily stop treatment. In other embodiments, energy deliveryalgorithms can be varied in real-time to account for changes detecteddue to patient and/or arterial movement. In further examples, thetreatment device may include one or more modifications or movementresistant enhancements such as atraumatic friction knobs or barbs on anoutside surface of the device for resisting movement of the devicerelative to the desired tissue location, positionable balloons forinflating and holding the device in a consistent and stable positionduring treatment, or the device can include a cryogenic component thatcan temporarily freeze or adhere the device to the desired tissuelocation.

After accessing a renal artery and facilitating stable contact betweenneuromodulatory apparatus and a luminal surface of the artery, nerves inand around the adventitia of the artery can be modulated via theneuromodulatory apparatus. In further embodiments, energy can be appliedvia the neuromodulatory apparatus to renal perivascular adipose tissuepositioned adjacent to the targeted renal artery. Effectively applyingthermal treatment from within a renal artery is non-trivial given thepotential clinical complications associated with such treatment. Forexample, the intima and media of the renal artery are highly vulnerableto thermal injury. As discussed in greater detail below, theintima-media thickness separating the vessel lumen from its adventitiameans that target renal nerves may be multiple millimeters distant(e.g., 1-3 mm) from the luminal surface of the artery. Sufficient energycan be delivered to or heat removed from the target renal nerves tomodulate the target renal nerves without excessively cooling or heatingthe vessel wall to the extent that the wall is frozen, desiccated, orotherwise potentially affected to an undesirable extent. For example,when employing energy modalities such as RF or ultrasound, energydelivery can be focused on a location further from the interior vesselwall. In one embodiment, the majority of the RF or ultrasound energy canbe focused on a location (e.g., a “hot spot”) 1-3 mm beyond the interiorsurface of the vessel wall. The energy will dissipate from the hot spotin a radially decreasing manner. Thus, the targeted nerves can bemodulated without damage to the luminal surface of the vessel. Apotential clinical complication associated with excessive heating isthrombus formation from coagulating blood flowing through the artery.Given that this thrombus may cause a kidney infarct, thereby causingirreversible damage to the kidney, thermal treatment from within therenal artery RA can be applied carefully. Accordingly, the complex fluidmechanics and thermodynamic conditions present in the renal arteryduring treatment, particularly those that may impact heat transferdynamics at the treatment site, may be important in applying energy(e.g., heating thermal energy) and/or removing heat from the tissue(e.g., cooling thermal conditions) from within the renal artery.Accordingly, sensory feedback, such as impedance and temperature, can beused to assess whether a desired energy distribution is administered atthe treatment site and can, in some instances, be used to change anenergy delivery algorithm in real-time to adjust for varyingfluctuations in the properties and conditions affecting heat transferdynamics at the treatment site.

The neuromodulatory apparatus can also be configured to allow foradjustable positioning and repositioning of an energy delivery elementor a cryotherapeutic device, within the renal artery since location oftreatment may also impact clinical efficacy. For example, it may betempting to apply a full circumferential treatment from within the renalartery given that the renal nerves may be spaced circumferentiallyaround a renal artery. In some situations, full-circle lesion likelyresulting from a continuous circumferential treatment may be potentiallyrelated to renal artery stenosis. Therefore, the formation of morecomplex lesions along a longitudinal dimension of the renal artery viathe cryotherapeutic devices or energy delivery elements and/orrepositioning of the neuromodulatory apparatus to multiple treatmentlocations may be desirable. It should be noted, however, that a benefitof creating a circumferential lesion or ablation may outweigh thepotential of renal artery stenosis or the risk may be mitigated withcertain embodiments or in certain patients and creating acircumferential lesion or ablation could be a goal. Additionally,variable positioning and repositioning of the neuromodulatory apparatusmay prove to be useful in circumstances where the renal artery isparticularly tortuous or where there are proximal branch vessels off therenal artery main vessel, making treatment in certain locationschallenging.

Blood flow through a renal artery may be temporarily occluded for ashort time with minimal or no complications. However, occlusion for asignificant amount of time can be avoided in some cases to preventinjury to the kidney such as ischemia. It can be beneficial to avoidocclusion altogether or, if occlusion is beneficial, to limit theduration of occlusion, for example to 2-5 minutes.

C. Neuromodulation of Renal Sympathetic Nerve at Treatment Site

FIG. 5 illustrates modulating renal nerves with an embodiment of thesystem 10 (FIG. 3 ). The treatment device 12 provides access to therenal plexus RP through an intravascular path P, such as a percutaneousaccess site in the femoral (illustrated), brachial, radial, or axillaryartery to a targeted treatment site within a respective renal artery RA.As illustrated, a section of the proximal portion 18 of the shaft 16 isexposed externally of the patient. By manipulating the proximal portion18 of the shaft 16 from outside the intravascular path P, the clinicianmay advance the shaft 16 through the sometimes tortuous intravascularpath P and remotely manipulate the distal portion 20 of the shaft 16.Image guidance, e.g., CT, fluoroscopy, intravascular ultrasound (IVUS),optical coherence tomography (OCT), or another suitable guidancemodality, or combinations thereof, may be used to aid the clinician'smanipulation. Further, in some embodiments, image guidance components(e.g., IVUS, OCT) may be incorporated into the treatment device 12. Insome embodiments, the shaft 16 and the neuromodulation assembly 21 canbe 3, 4, 5, 6, or 7 French or another suitable size. Furthermore, theshaft 16 and the neuromodulation assembly 21 can be partially or fullyradiopaque and/or can include radiopaque markers corresponding tomeasurements, e.g., every 5 cm.

After the neuromodulation assembly 21 is adequately positioned in therenal artery RA, it can be radially expanded or otherwise deployed usingthe handle 34 or other suitable control mechanism until theneuromodulation assembly is positioned at its target site and in stablecontact with the inner wall of the renal artery RA. The purposefulapplication of energy from the neuromodulation assembly can then beapplied to tissue to induce one or more desired neuromodulating effectson localized regions of the renal artery RA and adjacent regions of therenal plexus RP, which lay intimately within, adjacent to, or in closeproximity to the adventitia of the renal artery RA. For example, theapplication of energy can be applied to renal neural tissue or to renalperivascular adipose tissue that within, adjacent to, or in closeproximity to the adventitia of the renal artery RA. The neuromodulatingeffects may include denervation, thermal ablation, and non-ablativethermal alteration or damage (e.g., via sustained heating and/orresistive heating). The purposeful application of the energy may achieveneuromodulation along all or at least a portion of the renal plexus RP.In targeting the renal perivascular adipose tissue, the effects of theenergy delivery may achieve thermal ablation or non-ablative thermalalteration or damage to such cells. While delivery of energy to alter ordamage renal perivascular adipose tissue has been discussed, it is alsoanticipated that other types of cell-altering or damaging therapies(e.g., delivery of chemical agents) can be used.

In the deployed state, the neuromodulation assembly 21 can be configuredto contact an inner wall of a vessel of the renal vasculature and toform a suitable lesion or pattern of lesions without the need forrepositioning. For example, the neuromodulation assembly 21 can beconfigured to form a single lesion or a series of lesions, e.g.,overlapping and/or non-overlapping. In some embodiments, the lesion(s)(e.g., pattern of lesions) can extend around generally the entirecircumference of the vessel, but can still be non-circumferential atlongitudinal segments or zones along a lengthwise portion of the vessel.This can facilitate precise and efficient treatment with a lowpossibility of vessel stenosis. In other embodiments, theneuromodulation assembly 21 can be configured form apartially-circumferential lesion or a fully-circumferential lesion at asingle longitudinal segment or zone of the vessel. During treatment, theneuromodulation assembly 21 can be configured for partial or fullocclusion of a vessel. Partial occlusion can be useful, for example, toreduce ischemia, while full occlusion can be useful, for example, toreduce interference (e.g., warming or cooling) caused by blood flowthrough the treatment location. In some embodiments, the neuromodulationassembly 21 can be configured to cause therapeutically-effectiveneuromodulation (e.g., using ultrasound energy) without contacting avessel wall.

As mentioned previously, the methods disclosed herein may use a varietyof suitable energy modalities, including RF energy, pulsed RF energy,microwave energy, laser, optical energy, ultrasound energy (e.g.,intravascularly delivered ultrasound, extracorporeal ultrasound, HIFU),magnetic energy, direct heat, cryotherapy, radiation (e.g., infrared,visible, gamma), or a combination thereof. Alternatively or in additionto these techniques, the methods may utilize one or more non-ablativeneuromodulatory techniques. For example, the methods may utilizenon-ablative SNS neuromodulation by removal of target nerves (e.g.,surgically), injection of target nerves with a destructive drug orpharmaceutical compound, or treatment of the target nerves withnon-ablative energy modalities (e.g., laser or light energy). In certainembodiments, the amount of reduction of the sympathetic nerve activitymay vary depending on the specific technique being used.

In certain embodiments, a neuromodulation device for use in the methodsdisclosed herein may combine two or more energy modalities. For example,the device may include both a hyperthermic source of ablative energy anda hypothermic source, making it capable of, for example, performing bothRF neuromodulation and cryo-neuromodulation. The distal end of thetreatment device may be straight (for example, a focal catheter),expandable (for example, an expanding mesh or cryoballoon), or have anyother configuration. For example, the distal end of the treatment devicecan be at least partially helical/spiral in the deployed state.Additionally or alternatively, the treatment device may be configured tocarry out one or more non-ablative neuromodulatory techniques. Forexample, the device may comprise a means for diffusing a drug orpharmaceutical compound at the target treatment area (e.g., a distalspray nozzle).

Furthermore, a treatment procedure can include treatment at any suitablenumber of treatment locations, e.g., a single treatment location, twotreatment locations, or more than two treatment locations. In someembodiments, different treatment locations can correspond to differentportions of the renal artery RA, the renal vein, and/or other suitablestructures proximate tissue having relatively high concentrations ofrenal nerves. The shaft 16 can be steerable (e.g., via one or more pullwires, a steerable guide or sheath catheter, etc.) and can be configuredto move the neuromodulation assembly 21 between treatment locations. Ateach treatment location, the neuromodulation assembly 21 can beactivated to cause modulation of nerves proximate the treatmentlocation. Activating the neuromodulation assembly 21 can include, forexample, heating, cooling, stimulating, or applying another suitabletreatment modality at the treatment location. Activating theneuromodulation assembly 21 can further include applying various energymodalities at varying power levels, intensities and for variousdurations for achieving modulation of nerves proximate the treatmentlocation. In some embodiments, power levels, intensities and/ortreatment duration can be determined and employed using variousalgorithms for ensuring modulation of nerves at select distances (e.g.,depths) away from the treatment location. Furthermore, as notedpreviously, in some embodiments, the neuromodulation assembly 21 can beconfigured to introduce (e.g., inject) a chemical (e.g., a drug or otheragent) into target tissue at the treatment location. Such chemicals oragents can be applied at various concentrations depending on treatmentlocation and the relative depth of the target nerves.

As discussed, the neuromodulation assembly 21 can be positioned at atreatment location within the renal artery RA, for example, via acatheterization path including a femoral artery and the aorta, oranother suitable catheterization path, e.g., a radial or brachialcatheterization path. Catheterization can be guided, for example, usingimaging, e.g., magnetic resonance, computed tomography, fluoroscopy,ultrasound, intravascular ultrasound, optical coherence tomography, oranother suitable imaging modality. The neuromodulation assembly 21 canbe configured to accommodate the anatomy of the renal artery RA, therenal vein, and/or another suitable structure. For example, theneuromodulation assembly 21 can include a balloon (not shown) configuredto inflate to a size generally corresponding to the internal size of therenal artery RA, the renal vein, and/or another suitable structure. Insome embodiments, the neuromodulation assembly 21 can be an implantabledevice and a treatment procedure can include locating theneuromodulation assembly 21 at the treatment location using the shaft 16fixing the neuromodulation assembly 21 at the treatment location,separating the neuromodulation assembly 21 from the shaft 16, andwithdrawing the shaft 16. Other treatment procedures for modulation ofrenal nerves in accordance with embodiments of the present technologyare also possible.

FIG. 6 is a block diagram illustrating a method 600 of modulating renalnerves using the system 10 described above with reference to FIGS. 3 and5 . With reference to FIGS. 3, 5 and 6 together, the method 600 canoptionally include selecting a suitable candidate patient having anidentifiable eating disorder risk factor for performing renalneuromodulation (block 602). For example, a suitable patient can includea patient having an eating disorder risk score corresponding to aneating disorder status in the patient that is above a threshold level, apatient having one or more measurable risk factors for developing aneating disorder, a patient having one or more identifiable eatingdisorder symptoms, a patient diagnosed with an eating disorder, anat-risk patient having a history of an eating or other mental disorder(e.g., depression, anxiety disorder) and/or a genetic predisposition fordeveloping an eating disorder, and/or a patient with a history ofcardiovascular disease or stroke and having one or more identifiablerisk factors for developing an eating disorder.

Modulating SNS nerves innervating the kidneys is expected to lower renalnerve activity and/or central SNS nerve activity, thereby inhibiting,preventing, slowing, disrupting or reversing physiological pathwaysassociated with eating disorders and/or lowering a risk associated withdeveloping an eating disorder in the patient either before or afteron-set of one or more eating disorder symptoms. In particular, targetingthe renal nerve for neuromodulation is anticipated to reduce renalnorepinephrine spillover, whole body norepinephrine spillover, andreduce central sympathetic drive (e.g., reduce a level of efferent SNSnerve firing) in the patient, thereby inhibiting, preventing, slowing,disrupting or reversing an eating disorder and/or symptoms associatedwith an eating disorder and/or conditions proposed to increase apatient's risk of developing an eating disorder. Further, damaging renalperivascular adipose tissue is anticipated to reduce renalnorepinephrine spillover (e.g., released) from these cells. Withoutbeing bound by theory, renal neuromodulation is anticipated to addressthe hyperactivity of the SNS and/or the elevated SNS tone present inpatients with an eating disorder and/or patients having one or more riskfactors for developing an eating disorder. In other instances, andwithout being bound by theory, an overactive or hyperactive SNS isbelieved to be an underlying contributing cause of eating disorders andrenal neuromodulation is anticipated to prevent or prohibit thedevelopment of a hyperactive or overactive SNS in a patient prior to orsubsequent to experiencing an adverse life event or circumstance thatprecipitates, for example, excessive or chronic psychological stress. Insuch instances, eating disorders and/or eating disorder symptoms can beattenuated and/or avoided despite experiencing the stress-inducing,adverse life event or circumstance.

The method 600 can include intravascularly locating the neuromodulationassembly 21 in a delivery state (e.g., low-profile configuration) to afirst target site in or near a first renal blood vessel (e.g., firstrenal artery) or first renal ostium (block 605). The treatment device 12and/or portions thereof (e.g., the neuromodulation assembly 21) can beinserted into a guide catheter or sheath to facilitate intravasculardelivery of the neuromodulation assembly 21. In certain embodiments, forexample, the treatment device 12 can be configured to fit within an 8 Frguide catheter or smaller (e.g., 7 Fr, 6 Fr, etc.) to access smallperipheral vessels. A guide wire (not shown) can be used to manipulateand enhance control of the shaft 16 and the neuromodulation assembly 21(e.g., in an OTW or a RX configuration). In some embodiments, radiopaquemarkers and/or markings on the treatment device 12 and/or the guide wirecan facilitate placement of the neuromodulation assembly 21 at the firsttarget site (e.g., a first renal artery or first renal ostium of thepatient). In some embodiments, a contrast material can be delivereddistally beyond the neuromodulation assembly 21, and fluoroscopy and/orother suitable imaging techniques can be used to aid in placement of theneuromodulation assembly 21 at the first target site.

The method 600 can further include connecting the treatment device 12 tothe console 26 (block 610), and determining whether the neuromodulationassembly 21 is in the correct position at the target site and/or whetherthe neuromodulation assembly (e.g., electrodes or cryotherapy balloon)is functioning properly (block 615). Once the neuromodulation assembly21 is properly located at the first target site and no malfunctions aredetected, the console 26 can be manipulated to initiate application ofan energy field to the target site to cause electrically-induced and/orthermally-induced partial or full denervation of the kidney (e.g., usingelectrodes or cryotherapeutic devices). Accordingly, heating and/orcooling of the neuromodulation assembly 21 causes modulation of renalnerves at the first target site to cause partial or full denervation ofthe kidney associated with the first target site (block 620).

In one example, the treatment device 12 can be an RF energy emittingdevice and RF energy can be delivered through energy delivery elementsor electrodes to one or more locations along the inner wall of the firstrenal blood vessel or first renal ostium for predetermined periods oftime (e.g., 120 seconds). In some embodiments, multiple treatments(e.g., 4-6) may be administered in both the left and right renal bloodvessels (e.g., renal arteries) to achieve a desired coverage and/ordesired inhibition of sympathetic neural activity in the body.

In some embodiments, a treatment procedure can include applying asuitable treatment modality at a treatment location in a testing step(not shown) followed by a treatment step. The testing step, for example,can include applying the treatment modality at a lower intensity and/orfor a shorter duration than during the treatment step. This can allow anoperator to determine (e.g., by neural activity sensors and/or patientfeedback) whether nerves proximate the treatment location are suitablefor modulation. Performing a testing step can be particularly useful fortreatment procedures in which targeted nerves are closely associatedwith nerves that could cause undesirable side effects if modulatedduring a subsequent treatment step.

A technical objective of a treatment may be, for example, to heat tissueto a desired depth (e.g., at least about 3 mm) to a temperature thatwould lesion a nerve (e.g., about 65° C.). A clinical objective of theprocedure typically is to treat (e.g., lesion) a sufficient number ofrenal nerves (either efferent or afferent nerves) to cause a reductionin sympathetic tone or drive to the kidneys. If the technical objectiveof a treatment is met (e.g., tissue is heated to about 65° C. to a depthof about 3 mm) the probability of forming a lesion of renal nerve tissueis high. The greater the number of technically successful treatments,the greater the probability of modulating a sufficient proportion ofrenal nerves, and thus the greater the probability of clinical success.

In a specific example of using RF energy for renal nerve modulation, aclinician can commence treatment which causes the control algorithm 30(FIG. 3 ) to initiate instructions to the generator (not shown) togradually adjust its power output to a first power level (e.g., 5 watts)over a first time period (e.g., 15 seconds). The power increase duringthe first time period is generally linear. As a result, the generatorincreases its power output at a generally constant rate of power/time.Alternatively, the power increase may be non-linear (e.g., exponentialor parabolic) with a variable rate of increase. Once the first powerlevel and the first time are achieved, the algorithm may hold at thefirst power level until a second predetermined period of time haselapsed (e.g., 3 seconds). At the conclusion of the second period oftime, power is again increased by a predetermined increment (e.g., 1watt) to a second power level over a third predetermined period of time(e.g., 1 second). This power ramp in predetermined increments of about 1watt over predetermined periods of time may continue until a maximumpower P_(MAX) is achieved or some other condition is satisfied. In oneembodiment, P_(MAX) is 8 watts. In another embodiment P_(MAX) is 10watts. Optionally, the power may be maintained at the maximum powerP_(MAX) for a desired period of time or up to the desired totaltreatment time (e.g., up to about 120 seconds).

In another specific example, the treatment device 12 can be a cryogenicdevice and cryogenic cooling can be applied for one or more cycles(e.g., for 30 second increments, 60 second increments, 90 secondincrements, etc.) in one or more locations along the circumferenceand/or length of the first renal artery or first renal ostium. Thecooling cycles can be, for example, fixed periods or can be fully orpartially dependent on detected temperatures (e.g., temperaturesdetected by a thermocouple (not shown) of the neuromodulation assembly21). In some embodiments, a first stage can include cooling tissue untila first target temperature is reached. A second stage can includemaintaining cooling for a set period, such as 15-180 seconds (e.g., 90seconds). A third stage can include terminating or decreasing cooling toallow the tissue to warm to a second target temperature higher than thefirst target temperature. A fourth stage can include continuing to allowthe tissue to warm for a set period, such as 10-120 seconds (e.g., 60seconds). A fifth stage can include cooling the tissue until the firsttarget temperature (or a different target temperature) is reached. Asixth stage can include maintaining cooling for a set period, such as15-180 seconds (e.g., 90 seconds). A seventh stage can, for example,include allowing the tissue to warm completely (e.g., to reach a bodytemperature).

The neuromodulation assembly 21 can then be located at a second targetsite in or near a second renal blood vessel (e.g., second renal artery)or second renal ostium (block 625), and correct positioning of theassembly 21 can be determined (block 630). In selected embodiments, acontrast material can be delivered distally beyond the neuromodulationassembly 21 and fluoroscopy and/or other suitable imaging techniques canbe used to locate the second renal artery. The method 600 continues byapplying targeted heat or cold to effectuate renal neuromodulation atthe second target site to cause partial or full denervation of thekidney associated with the second target site (block 635).

After providing the therapeutically-effective neuromodulation energy(e.g., cryogenic cooling, RF energy, ultrasound energy, etc.), themethod 600 may also include removing the treatment device 12 (e.g.,catheter) and the neuromodulation assembly 21 from the patient (block640). In some embodiments, the neuromodulation assembly 21 can be animplantable device (not shown) and a treatment procedure can includeimplanting the neuromodulation assembly 21 at a suitable treatmentlocation within the patient. Other treatment procedures for modulationof target sympathetic nerves in accordance with embodiments of thepresent technology are also possible.

The method 600 may also include determining whether the neuromodulationsufficiently modulated nerves or other neural structures proximate thefirst and second target sites (block 645). For example, the process ofdetermining whether the neuromodulation therapeutically treated thenerves can include determining whether nerves were sufficientlymodulated or otherwise disrupted to reduce, suppress, inhibit, block orotherwise affect the afferent and/or efferent renal signals (e.g., byevaluation of suitable biomarkers, stimulation and recording of nervesignals, etc.). Examples of suitable biomarkers and their detection aredescribed in International Patent Application No. PCT/US2013/030041,filed Mar. 8, 2013, and International Patent Application No.PCT/US2015/047568, filed Aug. 28, 2015, the disclosures of which areincorporated herein by reference in their entireties. Other suitabledevices and technologies, such as endovascular intraoperative renalnerve monitoring devices are described in International PatentApplication No. PCT/US12/63759, filed Jan. 29, 2013, and incorporatedherein by reference in its entirety.

In a further embodiment, patient assessment could include determiningwhether the neuromodulation therapeutically treated the patient for oneor more symptoms associated with an eating disorder, e.g., core eatingdisorder symptoms (e.g., intense fear of gaining weight or becoming fat,behaviors that interfere with weight gain (e.g., calorie restriction,purging, use of laxatives, etc.), disturbance in the way one sees bodyweight or shape, eating large amount of food in a discrete amount oftime (e.g., within a 2 hour period), sense of lack of control overeating, eating until uncomfortably full, eating large amounts of foodwhen not feeling physically hungry, recurrent compensatory behavior toprevent weight gain (e.g., self-induced vomiting, misuse of laxatives,diuretics, or medications), fasting, excessive exercise, feeling ashamedor disgusted with oneself, or depressed, etc.), feelings of anxiety ordepression, systemic inflammation, and undesirable elevations in heartrate, blood pressure, and skin conductance, among others. Assessment ofcertain suitable biomarkers and/or nerve signals may be made immediatelyor shortly after neuromodulation (e.g., about 15 minutes, about 24hours, or about 7 days post-neuromodulation). In further embodiments,patient assessment could be performed at time intervals (e.g., about 1month, 3 months, 6 months, 12 months) following neuromodulationtreatment. For example, the patient can be assessed for measurements ofblood pressure, blood pressure variability, nocturnal blood pressure“dipping,” MSBP level, skin conductance, resting heart rate, measures ofsympathetic activity (e.g., MSNA, renal and/or total body norepinephrinespillover, plasma norepinephrine levels, and heart rate variability),peripheral inflammatory markers (e.g., IL-6, CRP, etc.), NPY level,measures of HPA axis function (e.g., glucocorticoid levels (e.g., inhair, urine, plasma, etc.), glucocorticoid resistance, CAR level, CRHlevel, etc.), sodium level, potassium level, plasma aldosteroneconcentration, plasma renin activity, aldosterone-to-renin ratio, saltsuppression, levels of components of the RAAS (e.g., angiotensinogen IIlevels), urinary Na⁺/K⁺ levels, markers of renal damage or measures ofrenal function (e.g. creatinine level, estimated glomerular filtrationrate, blood urea nitrogen level, creatinine clearance, cystatin-C level,NGAL levels, KIM-1 levels, presence of proteinuria or microalbuminuria,urinary albumin creatinine ratio), and/or a post-neuromodulation eatingdisorder risk score (e.g., via an eating disorder screening tool fordetermining a severity of an eating disorder).

In other embodiments, various steps in the method 600 can be modified,omitted, and/or additional steps may be added. In further embodiments,the method 600 can have a delay between applyingtherapeutically-effective neuromodulation energy to a first target siteat or near a first renal artery or first renal ostium and applyingtherapeutically-effective neuromodulation energy to a second target siteat or near a second renal artery or second renal ostium. For example,neuromodulation of the first renal artery can take place at a firsttreatment session, and neuromodulation of the second renal artery cantake place at a second treatment session at a later time.

FIG. 7 is a block diagram illustrating a method 900 for improving aneating disorder risk score for a patient in accordance with aspects ofthe present technology. In a first step, the method 700 can includedetermining an initial eating disorder risk score for a patient (block702). For example, one or more suitable eating disorder risk scorecalculating techniques or tools can be used to establish an eatingdisorder risk score corresponding to an eating disorder status in thepatient as described above. At decision block 704, the initial eatingdisorder risk score can be evaluated against a threshold risk score orvalue. If the initial eating disorder risk score is not above thethreshold risk score, there is no need to reduce the eating disorderrisk score for the patient at the current time and no treatment isselected to perform (block 706). In such a patient, a clinician mayrecommend monitoring the patient's eating disorder risk score over time.For example, a clinician can optionally determine an updated initialeating disorder risk score for the patient after a determined time lapse(e.g., 1 month, 2 months, 3 months, 6 months, 12 months, etc.) (block708). Following each eating disorder risk score evaluation (block 708),the patient's eating disorder risk score is evaluated against thethreshold risk score or value (decision block 704).

If the patient's eating disorder risk score from method step 702, orfrom the optional method step 708, is higher than the threshold riskscore, the method 700 can include performing a neuromodulation procedurein the patient (block 710). In one example, the patient can be asuitable candidate patient as identified in method step 602 of method600 described above, and the neuromodulation procedure can be performedas described in continuing steps of method 600. In other embodiments, aclinician can perform an alternative neuromodulation procedure at methodstep 710. For example, neuromodulation of other target (e.g., non-renal)sympathetic nerves or neuromodulation in a single renal blood vessel(e.g., renal artery) may be performed on the patient.

The method 700 is expected to improve the patient's eating disorder riskscore or reduce a probability of the patient developing an eatingdisorder. Optionally, the clinician can further determine apost-neuromodulation eating disorder risk score for the patient (block712). For example, the patient can be evaluated using the eatingdisorder risk score tool to assess the patient's post-neuromodulationeating disorder status or, alternatively, risk of developing an eatingdisorder. If the post-neuromodulation eating disorder risk score isdetermined for the patient in step 712, the method includes comparingthe post-neuromodulation eating disorder risk score to the initialeating disorder risk score (block 714). In determining if the method 700is successful, the post-neuromodulation eating disorder risk score islower than the patient's initial eating disorder risk score asdetermined in step 702 (or updated initial eating disorder risk score asdetermined in step 708). In some examples, the post-neuromodulationeating disorder risk score is lower than the initial eating disorderrisk score by about 5%, about 10%, about 20% or about 30%. In otherembodiments, the post-neuromodulation eating disorder risk score islower than the initial eating disorder risk score by more than 30%. Incertain embodiments, the post-neuromodulation eating disorder risk scorecan be lower than the threshold risk score.

VII. EXPERIMENTAL EXAMPLES Example 1

This section describes an example of the outcome of renalneuromodulation on human patients. A total of 45 patients (mean age of58±9 years) diagnosed with essential hypertension were treated withpercutaneous, catheter based renal nerve ablation. Treatment included RFenergy delivery to the renal artery using a single-electrode SymplicityFlex™ catheter that was commercially available outside the United Statesfrom Medtronic plc, of 710 Medtronic Parkway, Minneapolis, MN55432-5604. In this human trial, a radiotracer dilution method was usedto assess overflow of norepinephrine from the kidneys into circulationbefore and 15-30 days after the procedure in 10 patients. Bilateralrenal-nerve ablation resulted in a marked reduction in meannorepinephrine spillover from both kidneys: 47% (95% confidenceinterval) one month after treatment.

In a similar human trial where bilateral renal nerve ablation wasperformed in 70 patients, whole-body norepinephrine levels (i.e., ameasure of “total” sympathetic activity), fell by nearly 50% after renalnerve ablation and measurement of muscle sympathetic nerve activityshowed a drop of 66% over 6 months, further supporting the conclusionthat total sympathetic dive was reduced by the renal denervationprocedure in this patient group.

Example 2

Example 2 describes the outcome of catheter-based renal neuromodulationon human patients diagnosed with hypertension. Patients selected havinga baseline systolic blood pressure of 160 mm Hg or more (≥150 mm Hg forpatients with type 2 diabetes) and taking three or more antihypertensivedrugs, were randomly allocated into two groups: 51 assessed in a controlgroup (antihypertensive drugs only) and 49 assessed in a treated group(undergone renal neuromodulation and antihypertensive drugs).

Patients in both groups were assessed at 6 months. Office-based bloodpressure measurements in the treated group were reduced by 32/12 mm Hg(SD 23/11, baseline of 178/96 mm Hg, p<0.0001), whereas they did notdiffer from baseline in the control group (change of 1/0 mm Hg, baselineof 178/97 mm Hg, p=0.77 systolic and p=0.83 diastolic). Between-groupdifferences in blood pressure at 6 months were 33/11 mm Hg (p<0.0001).At 6 months, 41 (84%) of 49 patients who underwent renal neuromodulationhad a reduction in systolic blood pressure of 10 mm Hg or more, comparedwith 18 (35%) of 51 control patients (p<0.0001).

Example 3

Example 3 describes the outcome of catheter-based renal neuromodulationon animal subjects in an additional experiment. In this example (andreferring to FIGS. 8A and 8B), studies using the pig model wereperformed using a multi-electrode Symplicity Spyral™ catheter or asingle-electrode Symplicity Flex™ catheter along with a Symplicity G3™generator. The catheters and generator were commercially available fromMedtronic plc in more than 50 countries outside the United States. Thecatheters were used in these cohorts of animals (n=66) to createmultiple RF ablations in the renal vasculature. Cortical axon density inthe renal cortex (FIG. 8A) and renal cortical norepinephrine (NE)concentration (FIG. 8B) were used as markers to measure proceduralefficacy.

As shown in FIG. 8A, cortical axon area (per mm²) dropped approximatelygreater than 54% between a control group (n=64) and treated groups ofpigs (n=66) undergoing treatment. For pigs undergoing treatment with theSymplicity Flex™ catheter (n=54), an average of 4.1 lesions were formedin each animal. These pigs demonstrated a 56.9% increase innon-functional axonal area along the renal artery, and a 68% decrease incortical axon area as compared with the control group. For pigsundergoing treatment with the Symplicity Spyral™ catheter (n=12), anaverage of 4.0 lesions were formed in each animal. The pigs undergoingtreatment with the Symplicity Spyral™ catheter demonstrated a 47.3%increase in non-functional area along the renal artery, and a 54%decrease in cortical axon area relative to the control group. Withoutbeing bound by theory, it is believed that the loss of cortical axons isa likely consequence of nerve atrophy distal to the ablation sites.

FIG. 8B includes (a) a graph of normalized cortical axon area vs. renalNE concentration, and (b) a graph of renal NE concentration vs. extent(%) of nerve ablation. Referring to the table of FIG. 10A and the twographs of FIG. 8B together, cortical axon area correlates directly withrenal NE. In particular, pigs undergoing treatment with the SymplicityFlex™ catheter exhibited a 65% decrease in mean NE level compared withthe pigs in the control group. The pigs treated with the SymplicitySpyral™ catheter exhibited a 68% decrease in mean NE level compared withthe pigs in the control group. This is further shown by the first graphof FIG. 8B, which demonstrates that a decrease in cortical axon areacorrelates with a decrease in NE levels. Referring to the second graphof FIG. 8B, renal NE decrease is non-linear with increased loss of nerveviability along the artery (further extent (%) of nerve ablation). Thesefindings suggest that catheter-based renal neuromodulation exhibits arelatively consistent impact on sympathetic nerve function andviability, and further suggest that neuromodulation of SNS fibersinnervating a target tissue and/or organ (such as the kidney) result ina significant decrease in local NE concentration.

Example 4

Example 4 describes an example of the outcome of renal neuromodulationon human patients. Markers of cardiovascular inflammation and remodelingwere assessed (Dörr, O., et al., Clin Res Cardiol, 2015, 104: 175-184).A total of 60 patients (mean age of 67.9±9.6 years) diagnosed withresistant arterial hypertension were treated with percutaneous,catheter-based renal sympathetic denervation. Treatment included RFenergy delivery to the renal artery using a Symplicity® catheter systemcommercially available outside the United States from Medtronic plc. Inthis human trial, a therapeutic response was defined as a systolic bloodpressure (BP) reduction of >10 mmHg in the office blood pressuremeasurement 6 months after renal denervation. Of the 60 patients, 49patients (82%) were classified as responders with a mean systolic BPreduction of >10 mmHg. Venous blood samples for determination ofbiomarkers of inflammation (e.g., IL-6, high-sensitive C-reactiveprotein (hsCRP)) and markers of vascular remodeling (matrixmetalloproteinases (MMP-2 and MMP-9), tissue inhibitors of matrixmetalloproteinases (TIMP-1)) were collected at baseline (prior to renaldenervation) and 6 months after renal denervation for all patients.

Collected data from all patients demonstrated that bilateral renal nervedenervation resulted in a significant reduction in mean office systolicBP of 26.4 mmHg (169.3±11.3 mmHg at baseline vs. 142.9±13.8 mmHg atfollow-up; p<0.001). The procedure further resulted in a significantreduction in the serum levels of hsCRP (3.6 mg/dL at baseline vs. 1.7mg/dL at follow-up, p<0.001), and a significant reduction in thepro-inflammatory cytokine IL-6 (4.04 pg/mL at baseline vs. 2.2 pg/mL atfollow-up, p<0.001) six months after treatment. Additionally, theprocedure resulted in a significant increase in the serum levels ofMMP-9 (425.2 ng/mL at base line vs. 574.1 ng/mL at follow-up, p=0.02),and in serum levels of MMP-2 (192.3 ng/mL at baseline vs. 231.3 ng/mL atfollow-up, p<0.001). There were no significant changes in TIMP-1 6months after renal denervation. Notably, of non-responders (e.g.,patients with a BP reduction of <10 mmHg), serum levels of hsCRP stilldecreased (3.2 mg/dL at baseline vs. 2.4 mg/dL at follow-up, p=0.09),and serum levels of IL-6 still decreased (3.1 pg/mL at baseline vs. 2.7pg/mL at follow-up, p=0.16), although there was a significantly greaterbeneficial effect of renal denervation on biomarker levels in BPresponders when compared with non-responders.

These findings suggest that catheter-based renal neuromodulationexhibits a positive vascular and systemic effect on mediators ofinflammation, IL-6 and hsCRP, and inhibitors (MMP-9 and MMP-2) ofdeleterious cardiovascular remodeling. Low serum levels of MMP-9 andMMP-2 have been found to be essential to damaging vascular remodelingfound in essential hypertension and progression of end-organ damageThese findings suggest that levels of MMP-9 and MMP-2, which areinvolved in ECM turnover in different tissues, including the arterialwall, can be elevated post-renal neuromodulation, and, without beingbound by theory, are postulated to be beneficial in reversal of damageto the vessels caused by inflammation, cardiovascular disease and/orhypertension. As elevated inflammatory biomarkers, such as IL-6 and CRP,have been proposed as predictors and possible contributors of eatingdisorder etiology and/or incidence of an eating disorder, these resultsdemonstrate that renal neuromodulation may be useful to reduce aseverity of an eating disorder, reverse an eating disorder diagnosis, orreduce a risk associated with the development of an eating disorder insusceptible or at risk patients. In addition to lowering systolic BP in(responsive) hypertensive patients, these findings suggest that renaldenervation has a positive effect on biomarkers of inflammation (e.g.,IL-6, hsCRP) and cardiovascular remodeling (e.g., MMP-2, MMP-9) separatefrom and in addition to the effect on blood pressure.

Example 5

Example 5 describes an example of the effects of renal neuromodulationon nocturnal blood pressure using ambulatory 24-hour blood pressure (BP)monitoring in human patients. Elevated blood pressure during thenighttime as well as early morning hours (e.g., elevated morning surgein BP; “MSBP”) is associated with an increased risk of cardiovascularevents and strokes, and MSBP is associated with sleep disordersindependent from “non-dipping” nocturnal blood pressure, with highermorning surges associated with higher levels of sleep disturbancesymptoms, including poorer overall sleep quality (FitzGerald, L., etal., J Hum Hypertens, 2012, 26: 228-235; Kario, K., et al.,Hypertension, 2015, 66:1130-1137; Kario, K. and Hamasaki, H., J ClinHypertens, 2015, 17: 682-685). In this example, a total of 576 patientsdiagnosed with resistant arterial hypertension (e.g., baseline officesystolic BP≥160 mm Hg and 24-hour ambulatory systolic BP≥135 mm Hg) wereeither treated (“RDN treated”; n=382) with bilateral percutaneous,catheter-based renal sympathetic denervation (mean age of 58±11 years)or blindly treated (“blind control”; n=159) with a sham procedure (e.g.,renal angiogram) or not treated (“control”; n=19) (Kario, K., et al.,Hypertension, 2015, 66:1130-1137). Treatment included RF energy deliveryto the renal artery using a Symplicity™ catheter system (Medtronic plc).The renal neuromodulation (“RDN”) treated group received up to sixablations rotated in 45 degree increments and approximately 5 mm apartfor 2 minutes each in both renal arteries. Treatments were deliveredfrom the first distal main renal artery bifurcation to the ostiumproximally and were spaced longitudinally and rotationally underfluoroscopic guidance. BP variability, morning ambulatory, nighttimeambulatory and daytime ambulatory systolic BP was measured by 24-hourambulatory BP monitoring before renal denervation and at 6 months afterrenal denervation.

In patients with resistant hypertension, renal denervation resulted insignificant reduction in ambulatory nighttime and morning BP. Forexample, mean ambulatory nighttime BP measurements in the RDN treatedgroup were reduced by 6.3±18.2 mm Hg (p<0.001; baseline of 151.5±18.3 mmHg, p=0.24), whereas they were not significantly reduced (−1.7±19.2 mmHg; p=0.233) from baseline (149.5±20.1 mm Hg, p=0.24) in the blindcontrol+control group 6 months post-neuromodulation. Further, meanambulatory morning BP measurements in the RDN treated group were reducedby 7.3±19.6 mm Hg (p<0.001; baseline of 161.2±17.2 mm Hg, p=0.24),whereas they were not significantly reduced (−3.2±21.0 mm Hg; p=0.046)from baseline (160.3±19.2 mm Hg, p=0.579) in the blind control+controlgroup 6 months post-neuromodulation. These findings suggest thatpatients presenting with an eating disorder and treated with renalneuromodulation will have decreased ambulatory nighttime systolic BP anddecreased MSBP which will reduce the patient's likelihood (e.g., lowerlevel of risk) of developing, progressing or worsening cardiovasculardisease. These findings further suggest that patients with an eatingdisorder and treated with renal neuromodulation will improve one or moresymptoms relating to the eating disorder.

Example 6

Example 6 describes a method for treating human patients diagnosed withan eating disorder with renal neuromodulation and anticipated outcomesof such treatment. In this example, human patients diagnosed with aneating disorder will be treated with renal denervation and a method oftreatment includes modulating nerve tissue surrounding the main renalartery (e.g., locations along the main renal vessel, locations at ornear the bifurcation, etc.) and/or modulating nerve tissue surroundingone or more primary branch trunks (e.g., proximal portion of one or moreprimary branch vessels distal to the bifurcation).

For patients undergoing distal main renal artery treatment, modulatingnerve tissue includes forming a plurality of spaced-apart lesions at thedistal segment of the renal artery and within a distance ofapproximately 6 mm proximal to the branch point within the renal arteryusing the Symplicity Spyral™ catheter, commercially available outsidethe United States from Medtronic plc. For example, a first (e.g., mostdistal) lesion can be formed about 5-6 mm proximal from the bifurcation.Other multi-electrode, spiral/helical-shaped catheters for formingmultiple lesions along the length of the vessel are also contemplatedfor these methods. For patients undergoing main artery treatment at acentral segment of the main renal artery, the Symplicity Spyral™catheter can be used to form a plurality of spaced-apart lesions (e.g.,about 2 lesions to about 4 lesions) in a spiral/helical pattern alongthe central segment of the main renal artery. The catheter may also bemoved proximally and/or distally to form multiple sets of lesions duringa procedure.

For patients undergoing renal branch treatment, modulating nerve tissueincludes forming up to about four lesions (e.g., about 2 lesions toabout 4 lesions) in one or more primary branch trunks (e.g., from about1 mm to about 6 mm distal to the primary bifurcation, in regions greaterthan 2 mm distal to the primary bifurcation). Modulation of nerve tissueat branch trunk treatment sites and/or different combinations oftreatment sites within the renal vasculature (e.g., locations along themain renal vessel, locations at or near the bifurcation, etc.) can alsobe performed using the multi-electrode Symplicity Spyral™ catheter.Other multi-electrode, spiral/helical-shaped catheters having a tighterspiral/helix (e.g., smaller pitch) for forming multiple lesions close inproximity along the length of the vessel are contemplated for thesemethods.

In a particular example, a method for efficaciously neuromodulatingrenal nerve tissue in a human patient can include advancing amulti-electrode Symplicity Spyral™ catheter to a first renal arterybranch vessel approximately 6 mm distal to the bifurcation. Followingretraction of a guidewire and/or straightening sheath, the SymplicitySpyral™ catheter can transform to a spiral/helically-shapedconfiguration that accommodates the inner diameter of a typical renalartery and/or the branches of the renal artery (e.g., about 2-10 mm),placing the electrodes (e.g., 4 electrodes) in contact with the vesselwall. A first (e.g., most distal) lesion can be formed about 5-6 mmdistal to the bifurcation. Following treatment at the first renal arterybranch, the catheter can be withdrawn into the main renal vessel andthen advanced under fluoroscopy into a second renal artery branch andthe treatment procedure can be repeated. Some methods can includetreating two branch vessels at the proximal trunk segment of the branchvessel. Other methods can include treating greater than two or all ofthe primary branch vessels branching from the main renal vessel (e.g.,distal to a primary bifurcation). As described above, these methods mayalso include combining neuromodulation of renal nerve tissue surroundingone or more primary branch trunks with neuromodulation of renal nervetissue at additional treatment locations (e.g., locations along the mainrenal vessel, locations at or near the bifurcation, etc.). Other methodscan include advancing a multi-electrode Symplicity Spyral™ catheter to afirst renal artery branch vessel approximately 10 mm distal to thebifurcation, with a first (e.g., most distal) lesion formed about 9-10mm distal to the bifurcation.

Physiological biomarkers, such as systemic catecholamines and/or theirsubsequent degradation products could be measured in either plasma,serum or urine to serve as surrogate markers to measure proceduralefficacy such as described in International Patent Application No.PCT/US2015/047568, filed Aug. 28, 2015, and incorporated herein byreference in its entirety.

It is anticipated that treating a human patient diagnosed with an eatingdisorder or having an increased risk of developing an eating disorder(e.g., a predisposition, having one or more biomarkers suggesting anincreased likelihood, genetic/epigenetic factors, etc.) or having one ormore measurable risk factors predictive for the development of an eatingdisorder, with renal neuromodulation, at one or more of the describedtreatment locations, will inhibit sympathetic neural activity in therenal nerve in a manner that reduces a central sympathetic drive (e.g.,as correlated with whole body norepinephrine spillover and/or renalnorepinephrine spillover) by greater than about 20%, about 30%, about40%, about 50% or greater than about 60% in about 1 month, in about 3months, in about 6 months or in about 12 months, or in anotherembodiment, in about 3 months to about 12 months, after renalneuromodulation treatment. Reduction in central sympathetic drive isanticipated to result in a therapeutically beneficial improvement in oneor more measurable physiological parameters corresponding to anincidence of an eating disorder, and/or a severity of an eating disorderin the patient.

Example 7

Example 7 describes a method for determining human patients who have acalculated risk score for determining an eating disorder status (e.g.,diagnosis) at or above a threshold eating disorder risk score andtreating such patients with targeted sympathetic neuromodulation ofrenal SNS neural fibers innervating the kidney. In this example, humanpatients having a calculated eating disorder risk score meeting orexceeding a threshold eating disorder risk score will be treated withrenal neuromodulation to improve the patient's eating disorder riskscore and/or lower the patient's eating disorder risk score (e.g., in amanner that improves the patient's eating disorder status, reverses thepatient's eating disorder diagnosis, and/or improves one or moresymptoms or contributing factors associated with the eating disorder inthe patient).

Patients presenting one or more risk factors or indicators predictivefor or indicative of an eating disorder will be assessed for otherpossible risk factors and an eating disorder risk score will becalculated. In this example, a patient will fill out a questionnaire orotherwise have an attending physician assess risk factors. An eatingdisorder risk score calculator based on risk factor data to determine aprobability or likelihood of eating disorder status (e.g., diagnosis) inan individual is shown in FIG. 9 . The eating disorder risk scorecalculator shown in FIG. 9 is derived from data provided in the EDE-Qstudy to develop a model of a technique to assess duration and/orfrequency of eating disorder symptoms and screen the patient for riskfactors and indicators of an eating disorder to determine a likelihoodand/or severity of an eating disorder diagnosis.

Referring to the eating disorder risk score calculator shown in FIG. 9 ,a patient will be queried and assessed for core eating disorderindicators (e.g., deliberately trying to limit the amount of food eaten(e.g., to influence one's shape or weight), having gone for long periodsof time (e.g., 8 waking hours or more) without eating, trying to excludefrom diet any liked foods, trying to follow definite rules regardingeating (e.g., calorie limit) in order to influence body shape or weight,having a definite desire to have an empty stomach with the aim ofinfluencing shape or weight, having a definite desire to have a totallyflat stomach, thinking about food and eating or calories making itdifficult to concentrate on previously interesting things (e.g., work,conversation, reading, etc.), thinking about shape or weight making itdifficult to concentrate on interesting things, having a definite fearof losing control over eating, having a definite fear of gaining weight,having felt fat, having a strong desire to lose weight, etc.). Inaddition to these twelve clinical indicators, the patient may also beexamined and/or tested by a physician for determination of otherphysiological variables pertaining to the SNS such as, for example,heart rate variability, heart rate reactions to stress, whole body MSNAlevels (FIG. 9 ), and systolic blood pressure (e.g., daytime, nocturnaland morning surge) (not shown in FIG. 9 ). In this example, the input tothe calculator will yield both a patient-specific eating disorder riskscore as well as an indication as to whether RDN treatment isrecommended. In this example, the threshold eating disorder risk scoreis 26. An indication of RDN recommendation may be based on whether thepatient's eating disorder risk score is at or above the threshold eatingdisorder risk score, either alone or in combination with one or morephysician-administered tests assessing SNS activity or systolic bloodpressure level.

As illustrated in FIG. 9 , a hypothetical patient reports experiencing 2eating disorder indicators every day, 1 eating disorder indicator 23-27days, 3 eating disorder indicators 16-22 days, 1 eating disorderindicators 13-15 days, 3 eating disorder indicators 1-3 days, andindicated that 2 eating disorder indicators were not experienced (e.g.,over the past 28 days, 4 weeks). A physician-administered SNS testassessing heart rate variability indicated the patient's SDNN intervalswere less than the 50 ms threshold, and a test for baroreflex indicatedthat the baroreceptor sensitivity was less than 1.74 ms/mmHg; howeverthe patient did not exceed threshold levels in heart rate reactions tostress, and whole body MSNA levels. The hypothetical patient's eatingdisorder risk score of 35 exceeds the threshold level determination(e.g., greater than 25) for an eating disorder diagnosis. In thisexample, the eating disorder risk score together with meeting at leastone SNS threshold, qualifies the hypothetical patient as a candidate forreceiving RDN treatment. In another example, the hypothetical patient isa candidate for receiving RDN treatment with or without the additionalSNS tests (or ascertaining a systolic blood pressure for the patient).Following bilateral renal neuromodulation treatment, the hypotheticalpatient may have improvement in one or more measurable risk factors(e.g., heart rate variability, severity or frequency of anxietysymptoms, nocturnal and/or morning surge blood pressure, etc.), and/orreported risk factors pertaining to core eating disorder symptoms (e.g.,intense fear of gaining weight or becoming fat, behaviors that interferewith weight gain (e.g., calorie restriction, purging, use of laxatives,etc.), disturbance in the way one sees body weight or shape, eatinglarge amount of food in a discrete amount of time (e.g., within a 2 hourperiod), sense of lack of control over eating, eating untiluncomfortably full, eating large amounts of food when not feelingphysically hungry, recurrent compensatory behavior to prevent weightgain (e.g., self-induced vomiting, misuse of laxatives, diuretics, ormedications), fasting, excessive exercise, feeling ashamed or disgustedwith oneself, or depressed, etc.), that improves the patient's eatingdisorder risk score, and in some cases, to levels below the thresholdeating disorder risk score level(s).

VIII. FURTHER EXAMPLES

1. In a normotensive patient diagnosed with an eating disorder, a methodcomprising:

-   -   intravascularly positioning a neuromodulation assembly within a        renal blood vessel of the patient and adjacent to a renal nerve        of the patient; and    -   at least partially inhibiting sympathetic neural activity in the        renal nerve of the patient via the neuromodulation assembly,    -   wherein at least partially inhibiting sympathetic neural        activity results in a therapeutically beneficial improvement in        a measurable parameter associated with the eating disorder of        the patient.

2. The method of example 1 wherein the patient is diagnosed with bingeeating or bulimia nervosa, and wherein at least partially inhibitingsympathetic neural activity in the patient in a manner that results in atherapeutically beneficial improvement in a measurable parameterassociated with the eating disorder comprises one or more of reducing afrequency of binge eating episodes and reducing a frequency of purgingfollowing eating in the patient.

3. The method of example 1 or example 2 wherein the patient is diagnosedwith one or more of binge eating disorder, bulimia nervosa, anorexianervosa, pica disorder and rumination disorder.

4. The method of any one of examples 1-3 wherein reducing sympatheticneural activity in the patient in a manner that results in atherapeutically beneficial improvement in a measurable parameterassociated with the eating disorder comprises reducing a morning surgeblood pressure and/or a nocturnal blood pressure in the patient.

5. The method of example 1 wherein the patient is diagnosed withanorexia nervosa, wherein reducing sympathetic neural activity in thepatient in a manner that results in a therapeutically beneficialimprovement in a measurable parameter associated with the eatingdisorder comprises increasing the amount of food eaten by the patient.

6. The method of any one of examples 1-5 wherein reducing sympatheticneural activity in the patient further comprises improving one or moreeating disorder symptoms in the patient as reported on an eatingdisorder screening tool.

7. The method of example 6 wherein improving one or more eating disordersymptoms in the patient includes reducing a level of eating disordersymptoms and/or a number of eating disorder symptoms.

8. The method of example 6 or example 7 wherein improving one or moreeating disorder symptoms in the patient includes reducing a level ofeating disorder symptoms in the patient by at least about 5%, at leastabout 10%, at least about 20% or at least about 40%.

9. The method of example 6 or example 7 wherein improving one or moreeating disorder symptoms in the patient includes reducing a number ofeating disorder symptoms in the patient by at least about 5%, at leastabout 10%, at least about 20% or at least about 40% within about threemonths to about 12 months after at least partially inhibitingsympathetic neural activity in the patient by delivering energy to therenal nerve.

10. The method of any one of examples 1-9 wherein the patient is furtherdiagnosed with depression or an anxiety disorder.

11. The method of any one of examples 1-10 wherein the patient isbetween the ages of 18 and 45, between the ages of 18 and 30, betweenthe ages of 20 and 40, or between the ages of 20 and 35.

12. The method of any one of examples 1-10 wherein the patient isbetween the ages of 35 and 65, between the ages of 45 and 65, betweenthe ages of 50 and 70, or the patient is at least 35 years old.

13. The method of any one of examples 1-12 wherein at least partiallyinhibiting sympathetic neural activity in the patient further comprisesreducing an incidence of stroke or cardiovascular disease in thepatient.

14. The method of any one of examples 1-12 wherein the patient has ahistory of cardiovascular disease or stroke, and wherein at leastpartially inhibiting sympathetic neural activity in the patient furthercomprises reducing an incidence of a future cardiovascular event orstroke.

15. The method of example 1 wherein at least partially inhibitingsympathetic neural activity in the patient in a manner that results in atherapeutically beneficial improvement in a measurable parameterassociated with the eating disorder comprises improving a patient'seating disorder risk score on an eating disorder screening tool.

16. The method of any one of examples 1-15 wherein at least partiallyinhibiting sympathetic neural activity in the patient in a manner thatresults in a therapeutically beneficial improvement in a measurableparameter associated with the eating disorder includes one or more of:

-   -   increasing a heart rate variability of the patient;    -   increasing baroreceptor sensitivity in the patient;    -   reducing a morning surge blood pressure in the patient;    -   reducing a plasma cortisol level in the patient;    -   reducing a level of glucocorticoid resistance in the patient;        and    -   reducing a level of an inflammatory biomarker in the patient.

17. The method of example 16 wherein the inflammatory biomarker is atleast one of interleukin-6, interleukin-8, tumor necrosis factor-alpha,and C-reactive protein.

18. The method of any one of examples 1-17 wherein reducing sympatheticneural activity in the renal nerve further reduces muscle sympatheticnerve activity (MSNA) in the patient.

19. The method of any one of examples 1-18 wherein reducing sympatheticneural activity in the renal nerve further reduces whole bodynorepinephrine spillover in the patient.

20. The method of example 19 wherein the whole body norepinephrinespillover is reduced by at least about 20% in about one month or reducedby greater than about 40% in about three months to about 12 months afterreducing sympathetic neural activity in the renal nerve.

21. The method of example 1, further comprising delivering energy torenal perivascular adipose tissue adjacent to the renal blood vessel ofthe patient via the neuromodulation assembly to reduce norepinephrinespillover to plasma.

22. The method of any one of examples 1-21 wherein the patient iscurrently administered one or more pharmaceutical drugs for the eatingdisorder, and wherein at least partially inhibiting sympathetic neuralactivity in the patient in a manner that results in a therapeuticallybeneficial improvement in a measurable parameter associated with theeating disorder comprises reducing at least one of a number of or ameasured dosage of pharmaceutical drugs administered to the patient forthe eating disorder.

23. The method of example 22 wherein the pharmaceutical drugs includeone or more of an anti-anxiety drug, antidepressant, an anti-psychoticdrug, an insomnia drug, an obesity drug or an anti-inflammatory drug.

24. In a human patient, a method of reducing a risk of the patientdeveloping an eating disorder, the method comprising:

-   -   intravascularly positioning a catheter carrying a        neuromodulation assembly adjacent to a renal sympathetic nerve        of the patient;    -   delivering energy to the renal sympathetic nerve via the        neuromodulation assembly to attenuate neural traffic along the        renal sympathetic nerve; and    -   removing the catheter and neuromodulation assembly from the        patient after treatment,    -   wherein attenuating neural traffic along the renal sympathetic        nerve reduces a risk of the patient developing the eating        disorder.

25. The method of example 24 wherein the risk of developing the eatingdisorder is calculated using an eating disorder screening tool, andwherein a post-neuromodulation eating disorder risk score for thepatient, as calculated by the eating disorder screening tool, is lowerthan an initial eating disorder risk score.

26. The method of example 24 or example 25 wherein attenuating neuraltraffic along the renal sympathetic nerve further results in one or moreof:

-   -   increasing heart rate variability in the patient;    -   increasing baroreceptor sensitivity in the patient;    -   reducing a level of glucocorticoid resistance in the patient;    -   reducing a cortisol level in the patient;    -   reducing a systolic blood pressure of the patient;    -   reducing a morning surge blood pressure in the patient;    -   reducing a nocturnal blood pressure in the patient;    -   reducing muscle sympathetic nerve activity (MSNA) in the        patient;    -   reducing a plasma or urine norepinephrine level in the patient;        and    -   reducing a level of an inflammatory biomarker in the patient.

27. The method of example 26 wherein the inflammatory biomarker is atleast one of interleukin-6, interleukin-8, tumor necrosis factor-alpha,and C-reactive protein.

28. The method of any one of examples 24-27 wherein the patient has apersonal or family history of eating disorders, anxiety disorders and/ordepression, and wherein attenuating neural traffic along the renalsympathetic nerve reduces an incident of a future eating disorder in thepatient.

29. The method of any one of examples 24-28 wherein the patient iscurrently experiencing an adverse life circumstance and is diagnosedwith one or more of low heart rate variability, elevated plasma or urinecatecholamine levels, elevated systolic blood pressure, elevated morningsurge in blood pressure, non-dipping nocturnal blood pressure, lowneuropeptide Y level, elevated plasma cortisol level, glucocorticoidresistance, elevated cortisol awakening rise (CAR), reduced baroreceptorsensitivity, and elevated level of an inflammatory biomarker.

30. The method of any one of examples 24-29 wherein the patient has apolymorphism in at least one of the genes encoding for FK506-bindingprotein 5 (FKBP5 gene), glucocorticoid receptor (NR3C1 gene), cortisolreleasing hormone receptor-1 (CRHR1 gene), tumor necrosis factor(TNF)-alpha, that provide an increased likelihood of developing theeating disorder.

31. The method of any one of examples 24-30 wherein the patient isdiagnosed with cardiovascular disease.

32. The method of any one of examples 24-31 wherein the patient has ahistory of stroke.

33. The method of any of examples 24-32 wherein the patient has one ormore eating disorder risk factors selected from the group consisting ofincreased substance abuse, hypertension, elevated norepinephrine wholebody spillover, exposure to multiple traumatic events, female gender,family history of mental disorder, adverse childhood experience anddiagnosed with narcissistic personality disorder.

34. The method of any one of examples 24-33 wherein attenuating neuraltraffic along the renal sympathetic nerve comprises at least partiallyablating the renal sympathetic nerve.

35. The method of any one of examples 24-33 wherein attenuating neuraltraffic along the renal sympathetic nerve comprises at least partiallydisrupting communication along the renal sympathetic nerve.

36. The method of any one of examples 24-33 wherein attenuating neuraltraffic along the renal sympathetic nerve comprises irreversiblydisrupting communication along the renal sympathetic nerve.

37. The method of any one of examples 24-33 wherein attenuating neuraltraffic along the renal sympathetic nerve comprises delivering an energyfield to the renal sympathetic nerve via the neuromodulation assembly.

38. The method of example 37 wherein delivering an energy field to therenal sympathetic nerve comprises delivering at least one of radiofrequency energy, ultrasound energy, high intensity ultrasound energy,laser energy, and microwave energy via the neuromodulation assembly.

39. The method of any one of examples 24-38 wherein the patient isdiagnosed with prehypertension or hypertension, and wherein attenuatingneural traffic along the renal sympathetic nerve further reduces wholebody norepinephrine spillover in the patient in a manner that reducesthe risk of the patient developing the eating disorder.

40. A method for improving a patient's risk score corresponding to aneating disorder status of the patient, the method comprising:

-   -   intravascularly positioning a catheter carrying a        neuromodulation assembly within a renal blood vessel and        adjacent to a renal sympathetic nerve in the patient;    -   delivering energy to the renal sympathetic nerve via the        neuromodulation assembly to attenuate neural traffic along the        renal sympathetic nerve; and    -   removing the catheter and neuromodulation assembly from the        patient after treatment,    -   wherein attenuating neural traffic along the renal sympathetic        nerve results in improving the patient's risk score        corresponding to the eating disorder status of the patient.

41. The method of example 40 wherein improving the patient's risk scorecorresponding to the eating disorder status of the patient includes oneor more of improving eating disorder symptoms, reducing the patient'sanxiety level, reducing a level of systemic inflammation in the patient,and improving a patient's body mass index.

42. The method of example 40 or example 41 wherein the patient isdiagnosed with pre-hypertension or hypertension, and wherein improvingthe patient's risk score corresponding to the eating disorder status ofthe patient includes reducing the patient's blood pressure.

43. The method of any one of examples 40-42 wherein a patient's riskscore corresponding to the eating disorder status of the patient isreduced by at least about 10%, at least about 15%, at least about 20%,at least about 30% or at least about 40%.

44. The method of any one of examples 40-43 wherein the patient's riskscore is calculated using an eating disorder screening tool, and whereina post-neuromodulation eating disorder risk score, as calculated by theeating disorder screening tool, is lower than an initial eating disorderrisk score.

45. The method of example 44, wherein the eating disorder screening toolincludes an Eating Disorder Examination Questionnaire (EDE-Q) forassessing an eating disorder severity.

46. A method for improving an eating disorder risk score for a humanpatient diagnosed with an eating disorder, the method comprisingperforming a renal neuromodulation procedure in the patient diagnosedwith the eating disorder, wherein a post-neuromodulation risk score islower than an initial risk score of the patient diagnosed with theeating disorder.

47. The method of example 46 wherein the post-neuromodulation risk scoreis lower than the initial risk score by about 5%, about 10%, about 20%or about 30%.

48. The method of example 46 or example 47 wherein the initial riskscore indicates the patient is at risk of having the eating disorder ifthe initial risk score is greater than a threshold risk score.

49. The method of any one of examples 46-48 wherein the initial riskscore and the post-neuromodulation risk score are determined using aneating disorder screening tool for determining a severity of the eatingdisorder of the patient.

50. The method of any one of examples 46-49 wherein the initial riskscore and the post-neuromodulation risk score are based upon one or morefactors comprising a psychological evaluation, type and/or severity ofeating disorder symptoms, duration of eating disorder symptomsexperienced by the patient, number of instances of trauma exposure, andsymptoms associated with a mood disorder.

51. A method for managing an eating disorder in a normotensive humanpatient, the method comprising:

-   -   transluminally positioning an energy delivery element of a        catheter within a renal blood vessel of the patient and adjacent        to renal sympathetic neural fibers in the patient; and    -   at least partially ablating the renal sympathetic neural fibers        via the energy delivery element,    -   wherein at least partially ablating the renal sympathetic neural        fibers results in a therapeutically beneficial improvement in a        measurable parameter associated with the eating of the patient.

52. The method of example 51 wherein the patient is diagnosed with bingeeating or bulimia nervosa, wherein at least partially ablating the renalsympathetic neural fibers in the patient in a manner that results in atherapeutically beneficial improvement in a measurable parameterassociated with the eating disorder comprises one or more of reducing afrequency of binge eating episodes and reducing a frequency of purgingfollowing eating in the patient.

53. The method of example 51 or 52 wherein at least partially ablatingthe renal sympathetic neural fibers in the patient in a manner thatresults in a therapeutically beneficial improvement in a measurableparameter associated with the eating disorder comprises at least one ofreducing a nocturnal blood pressure and reducing a morning surge inblood pressure in the patient.

54. The method of any one of examples 51-53 wherein at least partiallyablating the renal sympathetic neural fibers in the patient in a mannerthat results in a therapeutically beneficial improvement in a measurableparameter associated with the eating disorder comprises improving one ormore eating disorder symptoms in the patient.

55. The method of any one of examples 51-54 wherein at least partiallyablating the renal sympathetic neural fibers further results in reducingan incidence of one or more of hypertension, cardiovascular disease,obesity, diabetes, insulin resistance, systemic inflammation, kidneydisease, stroke and dementia in the patient.

56. The method of any one of examples 51-55 wherein at least partiallyablating the renal sympathetic neural fibers further results in atherapeutically beneficial improvement in a measurable physiologicalparameter associated with a comorbid condition in the patient.

57. The method of example 56 wherein the comorbid condition is one ormore of depression, anxiety disorder, cancer, cardiovascular disease,obesity, metabolic disorder, systemic inflammation, dementia andinfertility.

58. The method of any one of examples 51-57, further comprisingadministering one or more pharmaceutical drugs to the patient, whereinthe pharmaceutical drugs are selected from the group consisting ofanti-insomnia drugs, anti-anxiety drugs, antidepressants,anti-hypertension drugs, anti-obesity drugs, and anti-inflammatorydrugs.

59. The method of any one of examples 51-58 wherein at least partiallyablating the renal sympathetic neural fibers of the patient via theenergy delivery element comprises delivering a thermal electric field tothe sympathetic neural fibers via at least one electrode.

60. A method for treating a patient that can answer affirmatively, ifasked, to at least two of the following statements:

-   -   in the past four weeks and at least most of the time—        -   a) you deliberately try limiting the amount of food you eat,        -   b) you have gone for long periods of time without eating            anything,        -   c) you have tried to exclude from your diet foods that you            like,        -   d) you have a definite desire to have an empty stomach,        -   e) you have a definite desire to have a totally flat            stomach,        -   f) thinking about food, eating or calories makes it            difficult concentrate,        -   g) thinking about shape or weight of your body makes it            difficult to concentrate,        -   h) you have a definite fear of losing control over eating,        -   i) you have a definite fear that you might gain weight,        -   j) you have felt fat, and        -   k) you have a strong desire to lose weight,            the method comprising:    -   intravascularly positioning a neuromodulation assembly within a        renal blood vessel of the patient and adjacent to a renal nerve        of the patient; and    -   at least partially inhibiting sympathetic neural activity in the        renal nerve of the patient via the neuromodulation assembly,    -   wherein at least partially inhibiting sympathetic neural        activity results in a therapeutically beneficial improvement in        the patient's response to one or more of statements a-k.

IX. CONCLUSION

The above detailed descriptions of embodiments of the technology andmethodology are not intended to be exhaustive or to limit the technologyto the precise forms disclosed above. Although specific embodiments of,and examples for, the technology are described above for illustrativepurposes, various equivalent modifications are possible within the scopeof the technology, as those skilled in the relevant art will recognize.For example, while steps are presented in a given order, alternativeembodiments may perform steps in a different order. The variousembodiments described herein may also be combined to provide furtherembodiments. All references cited herein are incorporated by referenceas if fully set forth herein.

From the foregoing, it will be appreciated that specific embodiments ofthe technology have been described herein for purposes of illustration,but well-known structures and functions have not been shown or describedin detail to avoid unnecessarily obscuring the description of theembodiments of the technology. Where the context permits, singular orplural terms may also include the plural or singular term, respectively.

Moreover, unless the word “or” is expressly limited to mean only asingle item exclusive from the other items in reference to a list of twoor more items, then the use of “or” in such a list is to be interpretedas including (a) any single item in the list, (b) all of the items inthe list, or (c) any combination of the items in the list. Additionally,the term “comprising” is used throughout to mean including at least therecited feature(s) such that any greater number of the same featureand/or additional types of other features are not precluded. It willalso be appreciated that specific embodiments have been described hereinfor purposes of illustration, but that various modifications may be madewithout deviating from the technology. Further, while advantagesassociated with certain embodiments of the technology have beendescribed in the context of those embodiments, other embodiments mayalso exhibit such advantages, and not all embodiments need necessarilyexhibit such advantages to fall within the scope of the technology.Accordingly, the disclosure and associated technology can encompassother embodiments not expressly shown or described herein.

We claim:
 1. A method comprising: determining a baseline measurement ofa measurable parameter associated with an eating disorder of a patient,wherein the patient is diagnosed with the eating disorder, and whereinthe measurable parameter comprises at least one of a norepinephrinecontent, a heart rate, a heart rate variability, a morning surge bloodpressure, a nocturnal blood pressure level, a systolic blood pressure, ablood pressure variability, baroreceptor sensitivity, skin conductance,or an inflammatory biomarker levels; at least partially ablating a renalnerve using a neuromodulation assembly positioned within a renal bloodvessel of the patient; determining a post-neuromodulation measurement ofthe measurable parameter; and comparing the post-neuromodulationmeasurement and the baseline measurement to determine a change in themeasurable parameter, wherein the change in the measurable parameterindicates a therapeutically beneficial improvement in at least one of afrequency of a symptom of the eating disorder, a level of severity ofthe eating disorder, or a number, type and/or duration of an eatingdisorder indication.
 2. The method of claim 1, wherein thetherapeutically beneficial improvement in the frequency of the symptomof the eating disorder indicates a reduction in the symptom of theeating disorder.
 3. The method of claim 1, wherein the patient isdiagnosed with binge eating or bulimia nervosa, and wherein the changein the measurable parameter indicates one or more of a reduced frequencyof binge eating episodes or a reduced frequency of purging followingeating by the patient following treatment.
 4. The method of claim 1,wherein the patient is diagnosed with anorexia nervosa, and wherein thechange in the measurable parameter indicates an amount of food eaten bythe patient is increased following treatment.
 5. The method of claim 1,wherein the patient is normotensive.
 6. The method of claim 1, whereindetermining the baseline measurement of the measurable parametercomprises determining the baseline measurement of the measurableparameter before at least partially ablating the renal nerve.
 7. Themethod of claim 1, wherein determining the baseline measurement of themeasurable parameter comprises determining the baseline measurementbased on a population of subjects.
 8. The method of claim 1, furthercomprising delivering energy to renal perivascular adipose tissueadjacent to the renal blood vessel of the patient via theneuromodulation assembly to reduce norepinephrine spillover.
 9. Themethod of claim 1, wherein at least partially ablating the renal nervecomprises delivering electrical energy, ultrasound energy, magneticenergy, or optical energy via the neuromodulation assembly positionedwithin the renal blood vessel.
 10. The method of claim 1, wherein atleast partially ablating the renal nerve comprises delivering a chemicalvia the neuromodulation assembly positioned within the renal bloodvessel.
 11. The method of claim 1, wherein at least partially ablatingthe renal nerve comprises thermally inducing modulation of the renalnerve via the neuromodulation assembly positioned within the renal bloodvessel.
 12. A method for treating a patient diagnosed with an eatingdisorder, the method comprising: determining a baseline measurement of ameasurable parameter associated with an eating disorder of a patient,wherein the patient is diagnosed with the eating disorder, and whereinthe measurable parameter comprises at least one of a norepinephrinecontent, a heart rate, a heart rate variability, a morning surge bloodpressure, a nocturnal blood pressure level, a systolic blood pressure, ablood pressure variability, baroreceptor sensitivity, skin conductance,or an inflammatory biomarker levels; delivering neuromodulation therapyto the patient via a neuromodulation assembly positioned within a renalblood vessel of the patient; determining a post-neuromodulationmeasurement of the measurable parameter; comparing thepost-neuromodulation measurement and the baseline measurement todetermine a change in the measurable parameter, wherein the change inthe measurable parameter indicates a therapeutically beneficialimprovement in at least one of a frequency of a symptom of the eatingdisorder, a level of severity of the eating disorder, or a number, typeand/or duration of an eating disorder indication; based on the change inthe measurable parameter, delivering further neuromodulation therapy tothe patient via the neuromodulation assembly positioned within the renalblood vessel of the patient.
 13. The method of claim 12, wherein theimprovement in the frequency of the symptom of the eating disorderindicates a reduction in a symptom of the eating disorder.
 14. Themethod of claim 12, wherein the patient is diagnosed with binge eatingor bulimia nervosa, and wherein the change in the measurable parameterindicates one or more of a reduced frequency of binge eating episodes ora reduced frequency of purging following eating by the patient followingtreatment.
 15. The method of claim 12, wherein the patient is diagnosedwith anorexia nervosa, and wherein the change in the measurableparameter indicates an amount of food eaten by the patient is increasedfollowing treatment.
 16. A method comprising: determining a baselinemeasurement of a measurable parameter associated with an eating disorderof a patient, wherein the patient is diagnosed with the eating disorder,and wherein the measurable parameter comprises at least one of skinconductance, a glucocorticoid level, glucocorticoid resistance, acardiac autonomic regulation level, a Neuropeptide Y level, acorticotropin-releasing hormone level, an inflammatory biomarker levels,or body mass index; at least partially ablating a renal nerve using aneuromodulation assembly positioned within a renal blood vessel of thepatient; determining a post-neuromodulation measurement of themeasurable parameter; and comparing the post-neuromodulation measurementand the baseline measurement to determine a change in the measurableparameter, wherein the change in the measurable parameter indicates animprovement in the measurable parameter associated with the eatingdisorder of the patient.
 17. The method of claim 16, wherein theimprovement in the measurable parameter indicates a reduction in asymptom of the eating disorder.
 18. The method of claim 16, wherein thepatient is diagnosed with binge eating or bulimia nervosa, and whereinthe change in the measurable parameter indicates one or more of areduced frequency of binge eating episodes or a reduced frequency ofpurging following eating by the patient following treatment.
 19. Themethod of claim 16, wherein the patient is diagnosed with anorexianervosa, and wherein the change in the measurable parameter indicates anamount of food eaten by the patient is increased following treatment.20. The method of claim 1, wherein the change in the measurableparameter associated with the eating disorder of the patient comprisesat least one of a decreased heart rate, an increased heart ratevariability, a reduced morning surge blood pressure, a decreasednocturnal blood pressure, a decreased systolic blood pressure, anincreased blood pressure variability, an increased baroreceptorsensitivity, a decreased skin conductance, or decreased inflammatorybiomarker levels.